**3. Gaucher's and Parkinson's disease: Theories of a link**

Parkinson's disease (PD) is the one of the common movement disorders and the second most common human neurodegenerative disease. The major diagnostic neuropathological

Role of Lysosomal Enzymes in Parkinson's Disease: Lesson from Gaucher's Disease 465

intracellular components (Levine & Klionsky, 2004). It can be induced also by hypoxia, neurotrophic factor deprivation, excitotoxins and accumulation of protein aggregates through PI3K and ERK-mediated pathways (Zhu t al., 2007; Boland & Nixon, 2006). Macroautophagy is described as the sequestration of complete regions of the cytosol, including not only soluble proteins, but also complete organelles, into a double membrane vescicle known as autophagosome, which is considered an immature form of autophagic vacuole (AV) (Seglen et al., 1996; Mortimore et al., 1996). The limiting double membrane is thought to arise from the endoplasmatic reticulum, although the Golgi complex has also been indicated as a source (Levine & Klionsky, 2004; Mijaljica et al., 2006). Because these vesicles lack any enzyme, the trapped contents are not degradated until the autophagosome

Macroautophagy is regulated by the action of a family of molecules, known as autophagyrelated proteins (Atg), which participates in each of the different steps of this process (Klionsky et al., 2003). A series of conjugation events (protein-to-lipid and protein-toprotein) and several members of intracellular kinase families are involved (Klionsky, 2005;

One hypotheses has been proposed to explain the role of dysregulated autophagy in PD pathogenesis, in patients affected to Gaucher's disease. This theory ("offensive metabolite theory") is based on the ceramide activity in the process of autophagic pathway modulation (Scarlatti et al., 2004). Ceramide is a sphingolipid mediator with an essential role in different situations correlated with authophagic system, such as cell growth, cell death, proliferation and stress response (Klionsky & Emr, 2000). Studies have shown as ceramide interferes with the inhibitory class I PI3K signaling pathway and induces the expression of a

It's possible that the lack of β-glucocerebrosidase activity and the accumulation of glucocerebroside may interfere with the ceramide modulation system, destroing cellular pathways necessary for autophagic-lysosomal degradation and leading to the LB formation. The other types of described autophagy are microautophagy and CMA. The first one consists of direct engulfment of small volumes of cytosol (constituted by soluble proteins but also by complete organelles) by lysosomes (Ahlberg et al., 1982) through invaginations or tabulations that "pinch off" from the membrane into the lysosomal lumen where they are rapidly degraded (Marzella et al., 1981). Microautophagy participates in the continuous turnover of long-lived proteins inside many types of cells (Mortimore et al., 1988); in addition a number of studies have shown as a particular form of microautophagy can lead to preferential degradation of peroxisomes (micropexophagy) (Farre and Subramani, 2004;

Chaperon-mediated autophagy is characterized by selectivity; about 30% of cytosolic proteins are degraded by this pathway. Through CMA particular cytosolic proteins are recognized by a chaperone in the cytosol, which delivers the proteins directly to the surface of the lysosome (Dice, 1990; Majeski & Dice, 2004, Massey et al., 2006). A distinctive feature of this pathway is that all substrate proteins contain in their amino acid sequence a motif, biochemically related to the pentapeptide KFERQ, required for targeting to the lysosomal compartment (Dice, 1990). A heat shock protein, hsc73 (Chiang et al., 1989) , recognizes the substrates containing the motif, and brings them to the lysosome membrane, where it binds to the receptor protein, lamp2 (lysosome-associated membrane protein type 2a) (Cuervo & Dice, 1996). The substrate interacts direcly with lamp2, and once unfolded, it is transported

founds with a lysosome, forming a single membrane autophagolysosome.

autophagy-related gene beclin 1, stimuling the autophagyc process.

in the lysosome lumen (Salvador et al., 2000) where it is degraded.

Mukaiyama et al., 2002; Veenhuis et al., 2000).

Ohsumi, 2001).

features of the pathologiy are loss of dopaminergic neurons and the appearance of Lewy bodies (LB), which are intraneuronal inclusions composed by α-synuclein and abnormal ubiquitinated proteins aggregates.

The first associations of the glucocerebrosidase enzyme with parkinsonism were discovered through careful clinical observation of people affecting by GD, who in several cases developed Parkinson's disease. Although in recent years GBA mutations were found to be a major risk factor for the development of Parkinson's disease (Sidransky et al., 2009), it is not clear how these are related. However many findings suggest that GBA protein and αsynuclein are implicated in a common cellular pathway and different hypothesis have been created to explain the linkage between them.

Recent studies have shown as some mutations in the GBA gene can lead to the misfolded protein formation (Sawkar et al., 2005), contributing to parkinsonism by leading to lysosomal insufficiency, as a result of impairing autophagic pathways necessary to prevent the synucleopathies, or by crushing the ubiquitin-proteasome system.

During the life span of a protein, cellular systems continuously check on the quality of the protein and take care of its repair or removal from the cell if there is any abnormality. The advancement during the past decades in understanding the quality control system of cellular proteins has allowed the identification of unequivocal links between malfunctioning of these systems and some severe human pathologies, including major neurodegenerative disease as Parkinson's (PD) and Alzheimer's (AD).

Many newly synthesized proteins are incorrectly translated or wrongly folded as a result of errors in their sequence due to either genetic mutations or alterations during the synthesis process (Wheatley & Inglis, 1980; Vabulas & Hartl, 2005; Shubert et al., 2000; Yewdell, 2005). The role of protein catabolism in protecting cells from defective, misfolded proteins is essential to avoid the risk of long term accumulation of proteins which frequently develop abnormal intermolecular interaction, forming insoluble aggregates toxic for the cells (Squier, 2001; Kourie & Henry, 2001). So it is evident the involvement of the quality control system in maintaining cell homeostasis as well as the association between the alteration of the protein turnover and many disease states (Kundu & Thompson, 2008). The autophagy-lysosome and the ubiquitin-proteasome pathways are the two main routes of the quality control system in eukaryotic.

Autophagy-lysosomal degradation pathway is a complex system tightly regulated by series of signaling events that promote the efficient delivery of macronutrients and organelles to lysosomes for degradation by acidic hydrolases (Levine & Klionsky, 2004). It is implicated in the catabolism and recycling of long-lived proteins and organelles and it is thought to be involved in many physiological processes, including the response to starvation, cell growth control, antiaging mechanisms and innate immunity. Some years ago the authophagylysosome pathway was considered as a non selective form of catabolism, while now the view is changed and it is thought as a specialized system that distinguishes the substrates and chooses the route by which they reach the lysosomes. Three types of autophagy have been described: macroautophagy, microautophagy and chaperon mediated autophagy (CMA) (Cuervo, 2004). They share a common endpoint, the lysosome, but differ in substrates targeted, their regulation and the conditions in which each of them is preferentially activated.

Macroautophagy process is activated to generate essential macromolecules and energy in condition of nutritional scarcity (Mizushima, 2005) or as a mechanism to remove the altered

features of the pathologiy are loss of dopaminergic neurons and the appearance of Lewy bodies (LB), which are intraneuronal inclusions composed by α-synuclein and abnormal

The first associations of the glucocerebrosidase enzyme with parkinsonism were discovered through careful clinical observation of people affecting by GD, who in several cases developed Parkinson's disease. Although in recent years GBA mutations were found to be a major risk factor for the development of Parkinson's disease (Sidransky et al., 2009), it is not clear how these are related. However many findings suggest that GBA protein and αsynuclein are implicated in a common cellular pathway and different hypothesis have been

Recent studies have shown as some mutations in the GBA gene can lead to the misfolded protein formation (Sawkar et al., 2005), contributing to parkinsonism by leading to lysosomal insufficiency, as a result of impairing autophagic pathways necessary to prevent

During the life span of a protein, cellular systems continuously check on the quality of the protein and take care of its repair or removal from the cell if there is any abnormality. The advancement during the past decades in understanding the quality control system of cellular proteins has allowed the identification of unequivocal links between malfunctioning of these systems and some severe human pathologies, including major neurodegenerative

Many newly synthesized proteins are incorrectly translated or wrongly folded as a result of errors in their sequence due to either genetic mutations or alterations during the synthesis process (Wheatley & Inglis, 1980; Vabulas & Hartl, 2005; Shubert et al., 2000; Yewdell, 2005). The role of protein catabolism in protecting cells from defective, misfolded proteins is essential to avoid the risk of long term accumulation of proteins which frequently develop abnormal intermolecular interaction, forming insoluble aggregates toxic for the cells (Squier, 2001; Kourie & Henry, 2001). So it is evident the involvement of the quality control system in maintaining cell homeostasis as well as the association between the alteration of the protein turnover and many disease states (Kundu & Thompson, 2008). The autophagy-lysosome and the ubiquitin-proteasome pathways are the two main routes of the quality control

Autophagy-lysosomal degradation pathway is a complex system tightly regulated by series of signaling events that promote the efficient delivery of macronutrients and organelles to lysosomes for degradation by acidic hydrolases (Levine & Klionsky, 2004). It is implicated in the catabolism and recycling of long-lived proteins and organelles and it is thought to be involved in many physiological processes, including the response to starvation, cell growth control, antiaging mechanisms and innate immunity. Some years ago the authophagylysosome pathway was considered as a non selective form of catabolism, while now the view is changed and it is thought as a specialized system that distinguishes the substrates and chooses the route by which they reach the lysosomes. Three types of autophagy have been described: macroautophagy, microautophagy and chaperon mediated autophagy (CMA) (Cuervo, 2004). They share a common endpoint, the lysosome, but differ in substrates targeted, their regulation and the conditions in which each of them is

Macroautophagy process is activated to generate essential macromolecules and energy in condition of nutritional scarcity (Mizushima, 2005) or as a mechanism to remove the altered

the synucleopathies, or by crushing the ubiquitin-proteasome system.

ubiquitinated proteins aggregates.

created to explain the linkage between them.

disease as Parkinson's (PD) and Alzheimer's (AD).

system in eukaryotic.

preferentially activated.

intracellular components (Levine & Klionsky, 2004). It can be induced also by hypoxia, neurotrophic factor deprivation, excitotoxins and accumulation of protein aggregates through PI3K and ERK-mediated pathways (Zhu t al., 2007; Boland & Nixon, 2006). Macroautophagy is described as the sequestration of complete regions of the cytosol, including not only soluble proteins, but also complete organelles, into a double membrane vescicle known as autophagosome, which is considered an immature form of autophagic vacuole (AV) (Seglen et al., 1996; Mortimore et al., 1996). The limiting double membrane is thought to arise from the endoplasmatic reticulum, although the Golgi complex has also been indicated as a source (Levine & Klionsky, 2004; Mijaljica et al., 2006). Because these vesicles lack any enzyme, the trapped contents are not degradated until the autophagosome founds with a lysosome, forming a single membrane autophagolysosome.

Macroautophagy is regulated by the action of a family of molecules, known as autophagyrelated proteins (Atg), which participates in each of the different steps of this process (Klionsky et al., 2003). A series of conjugation events (protein-to-lipid and protein-toprotein) and several members of intracellular kinase families are involved (Klionsky, 2005; Ohsumi, 2001).

One hypotheses has been proposed to explain the role of dysregulated autophagy in PD pathogenesis, in patients affected to Gaucher's disease. This theory ("offensive metabolite theory") is based on the ceramide activity in the process of autophagic pathway modulation (Scarlatti et al., 2004). Ceramide is a sphingolipid mediator with an essential role in different situations correlated with authophagic system, such as cell growth, cell death, proliferation and stress response (Klionsky & Emr, 2000). Studies have shown as ceramide interferes with the inhibitory class I PI3K signaling pathway and induces the expression of a autophagy-related gene beclin 1, stimuling the autophagyc process.

It's possible that the lack of β-glucocerebrosidase activity and the accumulation of glucocerebroside may interfere with the ceramide modulation system, destroing cellular pathways necessary for autophagic-lysosomal degradation and leading to the LB formation. The other types of described autophagy are microautophagy and CMA. The first one consists of direct engulfment of small volumes of cytosol (constituted by soluble proteins but also by complete organelles) by lysosomes (Ahlberg et al., 1982) through invaginations or tabulations that "pinch off" from the membrane into the lysosomal lumen where they are rapidly degraded (Marzella et al., 1981). Microautophagy participates in the continuous turnover of long-lived proteins inside many types of cells (Mortimore et al., 1988); in addition a number of studies have shown as a particular form of microautophagy can lead to preferential degradation of peroxisomes (micropexophagy) (Farre and Subramani, 2004; Mukaiyama et al., 2002; Veenhuis et al., 2000).

Chaperon-mediated autophagy is characterized by selectivity; about 30% of cytosolic proteins are degraded by this pathway. Through CMA particular cytosolic proteins are recognized by a chaperone in the cytosol, which delivers the proteins directly to the surface of the lysosome (Dice, 1990; Majeski & Dice, 2004, Massey et al., 2006). A distinctive feature of this pathway is that all substrate proteins contain in their amino acid sequence a motif, biochemically related to the pentapeptide KFERQ, required for targeting to the lysosomal compartment (Dice, 1990). A heat shock protein, hsc73 (Chiang et al., 1989) , recognizes the substrates containing the motif, and brings them to the lysosome membrane, where it binds to the receptor protein, lamp2 (lysosome-associated membrane protein type 2a) (Cuervo & Dice, 1996). The substrate interacts direcly with lamp2, and once unfolded, it is transported in the lysosome lumen (Salvador et al., 2000) where it is degraded.

Role of Lysosomal Enzymes in Parkinson's Disease: Lesson from Gaucher's Disease 467

The UPS can only degrade proteins when they are in a soluble state or as a part of reversible protein complexes that can be disassembled into single protein units (Finkbeiner et al., 2006; Kopito, 2000). So any type of irreversible oligomeric structures, preaggregates, and protein aggregates cannot be handled by UPS, instead they can be degraded by the autophagic-

A different theory ("misfolded protein theory") to explain the linkage between Gaucher's and Parkinson's disease, is that mutant misfolded glucocerebrosidase might overwhelm the UPS, causing a delay in the degradation of accumulated proteins, including α-synuclein (Dawson, 2006). Ron et al. have shown that misfolded GCase endures endoplasmatic reticulum associated degradation (ERAD) (Ron and Horowitz, 2005). In this process, mutant proteins are identified as misfolded by the ER quality control system and retrotraslocated from ER to cytosol, ubiquitinated and eliminated by the ubiquitin-proteasome system. The same authors proposed that mutated GBA protein (but not WT GBA) undergoes parkin (E3-ligase)-mediated ubiquitination, creating an imbalance in protein degradation resulting in secondary toxicity. It is likely that, since GCase is not a natural substrate of parkin, the enduringly ER retention and proteasomal degradation of mutant β-glucosidase, mediated by parkin, affect its activity toward its natural substrates. Accumulation during the years of these proteins can lead to the

The theories described above, cannot explain completely the correlation between the diseases. In the "offensive metabolite theory" the reducing of the released ceramide inhibits the autophagic-lysosomal functions. This can explain the development of LB and

Moreover in Gaucher patients where mutations in GBA result in no protein product (i.e. c.84dupG and IVS2+1G>A) the risk to develop PD is high. So the "misfolded protein theory" also cannot clear fully the question, even if it is probably that very truncated forms of the mutant protein still might induce endoplasmic reticulum stress and guide to crashing

The first indication of a relationship between parkinsonism and GD was due to sporadic case reports in the literarture (Neudorfer et al., 1996; Machaczka et al., 1999; Tayebi et al., 2001). In these papers it was highlighted how in some GD patients the enzyme deficiency

These observations of occurrence of Parkinson's disease in some patients with nonneuropathic type 1 Gaucher disease and in their first degree relatives has led to the identification of GBA1 heterozigous mutations as a genetic risk factor for idiopathic

In these subjects the mean age at onset of parkinsonian symptoms is lower than in patients without GD1, becoming evident at an average age of 48 years compared with 71 years in the

These early observations led to several studies which revealed that patients with idiopathic PD had a higher probability of harboring GBA1 mutations compared to the general

The first large study was conducted by Lwin et al. (2004), using sequence analyses on brain samples from 57 subjects of different nationality, GBA alterations were detected in 12

death of cells in substantia nigra and eventually, to the development of PD.

parkinsonism in Gaucher patients, but not in GBA mutations carriers.

**4. Genetic studies and neuropathological data** 

itself could predisposed to the susceptibility to parkinsonisms.

lysosomal pathway.

of UPS.

Parkinson's disease.

population.

sample (21%).

general population (Elbaz et al., 2003).

Substrates for CMA consist of a very heterogeneous pool of cytosolic proteins, different for structure and function, but having all the same KFERQ motif. CMA acts in the degradation of many different substrates (i.e. several glycolitic enzymes, glutathione transferase, ribonuclease A) and damaged proteins: its selective role allows removal of the altered proteins without affecting neighbouring healty ones (Kiffin et al., 2004; Cuervo et al., 1999). Many studies have shown as this autophagic pathway is activated when stress condition occurs in the cells, such as prolonged nutrient deprivation or exposure to toxic compounds (Cuervo & Dice, 1998).

Independently of the autophagic pathway, all substrates are brought to the lysosome lumen where several different lysosomal hydrolases rapidly degrade them. These enzymes are synthesized in the endoplasmatic reticulum, sorted to the trans-Golgi network by mannose-6-phosphate receptors, transported through the endosome to arrive to their lysosomal destination, where they are activated upon the exposure to the acid environment (Jadot et al., 1997). The proteolytic capacity of lysosomes comprises a mixture of endo- and exopeptidases, called cathepsins, which act in concert to degrade proteins to a mixture of amino acids and dipeptides. Expression, activation and inhibition of these cathepsins are differentially regulated, and individual cathepsins often have non-redundant functions in normal and disease states (Kroemer & Jaattela, 2005). In addition to peptidases activity, intralysosomal conditions and other lysosomal components (i.e. glycosidase, lipases, phospholipases, solphatases, nucleases and phosphatases) are designed to favor the complete degradation of the internalized products.

One route of degradation of the α-synuclein is via CMA pathway (Cuervo et al., 2004). Studies have revealed as impaired lysosomal function seems to be involved in familial forms of PD, as consequence of reduced α-synuclein degradation. So one theory is that disturbances in the lysosome (i.e. the alteration in the GCase function) contribute to reduce α-synuclein degradation and consequently promote its aggregation. This may be possible since ceramide can activate cathepsin D (aspartate protease), which in turn is responsible for the proteolytic activation of other lysosomal proteins (Heinrich et al., 1999). So the reduced activity of one protease can spark off the decremented action of other acid hydrolases causing an α-synuclein accumulation and contributing in LB formation.

The other α-synuclein degradation pathway is the ubiquitin-proteasome system (UPS). It serves as the primary route for the degradation of thousands of short-lived proteins and provides the specificity and temporal control needed for tuning the stady-state levels of many regulatory proteins (Ciechanover et al., 2000). UPS-mediated catabolism is also essential to preserve amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins (Ciechanover & Brudin, 2003; Whealtley & Inglis, 1980; Vabulas & Hartl, 2005). UPS contributes also to diverse cellular processes, such as protein quality control, cellcycle progression, signal transduction, and development (Kerscher et al., 2006).

Substrates of the ubiquitin/proteasome system (UPS) get post-translationally modified by covalent attachment of multiple ubiquitin molecules at internal lysine residues. This polyubiquitylation of substrate proteins involves three enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin protein ligases (E3). E1 hydrolyses ATP and forms a thioester-linked conjugate between itself and ubiquitin; E2 receives ubiquitin from E1 and forms a similar thioester intermediate with ubiquitin; and E3 binds both E2 and the substrate, and transfers the ubiquitin to the substrate. A chain made of four to six ubiquitin moieties targets the conjugated substrate for degradation by the 26S proteasome (Richly et al., 2005; Zhang et al., 2009).

Substrates for CMA consist of a very heterogeneous pool of cytosolic proteins, different for structure and function, but having all the same KFERQ motif. CMA acts in the degradation of many different substrates (i.e. several glycolitic enzymes, glutathione transferase, ribonuclease A) and damaged proteins: its selective role allows removal of the altered proteins without affecting neighbouring healty ones (Kiffin et al., 2004; Cuervo et al., 1999). Many studies have shown as this autophagic pathway is activated when stress condition occurs in the cells, such as prolonged nutrient deprivation or exposure to toxic compounds

Independently of the autophagic pathway, all substrates are brought to the lysosome lumen where several different lysosomal hydrolases rapidly degrade them. These enzymes are synthesized in the endoplasmatic reticulum, sorted to the trans-Golgi network by mannose-6-phosphate receptors, transported through the endosome to arrive to their lysosomal destination, where they are activated upon the exposure to the acid environment (Jadot et al., 1997). The proteolytic capacity of lysosomes comprises a mixture of endo- and exopeptidases, called cathepsins, which act in concert to degrade proteins to a mixture of amino acids and dipeptides. Expression, activation and inhibition of these cathepsins are differentially regulated, and individual cathepsins often have non-redundant functions in normal and disease states (Kroemer & Jaattela, 2005). In addition to peptidases activity, intralysosomal conditions and other lysosomal components (i.e. glycosidase, lipases, phospholipases, solphatases, nucleases and phosphatases) are designed to favor the

One route of degradation of the α-synuclein is via CMA pathway (Cuervo et al., 2004). Studies have revealed as impaired lysosomal function seems to be involved in familial forms of PD, as consequence of reduced α-synuclein degradation. So one theory is that disturbances in the lysosome (i.e. the alteration in the GCase function) contribute to reduce α-synuclein degradation and consequently promote its aggregation. This may be possible since ceramide can activate cathepsin D (aspartate protease), which in turn is responsible for the proteolytic activation of other lysosomal proteins (Heinrich et al., 1999). So the reduced activity of one protease can spark off the decremented action of other acid hydrolases

The other α-synuclein degradation pathway is the ubiquitin-proteasome system (UPS). It serves as the primary route for the degradation of thousands of short-lived proteins and provides the specificity and temporal control needed for tuning the stady-state levels of many regulatory proteins (Ciechanover et al., 2000). UPS-mediated catabolism is also essential to preserve amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins (Ciechanover & Brudin, 2003; Whealtley & Inglis, 1980; Vabulas & Hartl, 2005). UPS contributes also to diverse cellular processes, such as protein quality control, cell-

Substrates of the ubiquitin/proteasome system (UPS) get post-translationally modified by covalent attachment of multiple ubiquitin molecules at internal lysine residues. This polyubiquitylation of substrate proteins involves three enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin protein ligases (E3). E1 hydrolyses ATP and forms a thioester-linked conjugate between itself and ubiquitin; E2 receives ubiquitin from E1 and forms a similar thioester intermediate with ubiquitin; and E3 binds both E2 and the substrate, and transfers the ubiquitin to the substrate. A chain made of four to six ubiquitin moieties targets the conjugated substrate for degradation by the 26S

causing an α-synuclein accumulation and contributing in LB formation.

cycle progression, signal transduction, and development (Kerscher et al., 2006).

(Cuervo & Dice, 1998).

complete degradation of the internalized products.

proteasome (Richly et al., 2005; Zhang et al., 2009).

The UPS can only degrade proteins when they are in a soluble state or as a part of reversible protein complexes that can be disassembled into single protein units (Finkbeiner et al., 2006; Kopito, 2000). So any type of irreversible oligomeric structures, preaggregates, and protein aggregates cannot be handled by UPS, instead they can be degraded by the autophagiclysosomal pathway.

A different theory ("misfolded protein theory") to explain the linkage between Gaucher's and Parkinson's disease, is that mutant misfolded glucocerebrosidase might overwhelm the UPS, causing a delay in the degradation of accumulated proteins, including α-synuclein (Dawson, 2006). Ron et al. have shown that misfolded GCase endures endoplasmatic reticulum associated degradation (ERAD) (Ron and Horowitz, 2005). In this process, mutant proteins are identified as misfolded by the ER quality control system and retrotraslocated from ER to cytosol, ubiquitinated and eliminated by the ubiquitin-proteasome system. The same authors proposed that mutated GBA protein (but not WT GBA) undergoes parkin (E3-ligase)-mediated ubiquitination, creating an imbalance in protein degradation resulting in secondary toxicity. It is likely that, since GCase is not a natural substrate of parkin, the enduringly ER retention and proteasomal degradation of mutant β-glucosidase, mediated by parkin, affect its activity toward its natural substrates. Accumulation during the years of these proteins can lead to the death of cells in substantia nigra and eventually, to the development of PD.

The theories described above, cannot explain completely the correlation between the diseases. In the "offensive metabolite theory" the reducing of the released ceramide inhibits the autophagic-lysosomal functions. This can explain the development of LB and parkinsonism in Gaucher patients, but not in GBA mutations carriers.

Moreover in Gaucher patients where mutations in GBA result in no protein product (i.e. c.84dupG and IVS2+1G>A) the risk to develop PD is high. So the "misfolded protein theory" also cannot clear fully the question, even if it is probably that very truncated forms of the mutant protein still might induce endoplasmic reticulum stress and guide to crashing of UPS.
