**4. Genetic studies and neuropathological data**

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 itself could predisposed to the susceptibility to parkinsonisms.

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 Parkinson's disease.

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 general population (Elbaz et al., 2003).

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 population.

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 sample (21%).

Role of Lysosomal Enzymes in Parkinson's Disease: Lesson from Gaucher's Disease 469

Trying to find an answer to this issue, Gan-Or et al. (2008) performed a study analysing a large cohort of 420 unrelated Jewish Ashkenazi PD patients, which evidenced a strong correlation between GD1 and early-onset of PD symptoms (average age at onset of 51.2 years, versus 60.7 years of the noncarriers PD population), while GBA carriers showed an

They also analysed the different effects of mutation severity, observing a higher risk for PD in patients carrying severe GBA mutations as well as a decreased age of symptoms onset. Finally, when they analysed clinical PD manifestations among GBA carriers and noncarriers, they observed a reduced presence of rigidity (16.90% vs 28.57%) and an increase of

Another recent large observational study of 444 consecutive GD1 patients (Bultron et al., 2010), aiming to analyse the risk of PD occurrence, showed 11 patients (2.47%) who developed the disease at a mean age of 55.0 ± 8.8 years (range 40-65 years). Analysing GD overall severe score index (SSI) and bone disease score (Hermann score) in the overall population, they found both of them significantly higher in PD patients (SSI: 10.8±0.8 vs

Moreover, these authors estimated age and gender-adjusted risk to develop PD in three different groups of GD1 patients, finding that the range of risk was increased 11.0 to 31.3 fold in male patients and 5.7 to 13.8 fold in female patients, with an overall relative risk to

As regard the clinical response to ERT in GD1 patients with PD, all published experiences demonstrated its effectiveness on hematological and systemic involvement, while they were ineffective in correcting PD symptoms (Neudorfer et al., 1996; Tayebi et al, 2003; Bembi et al., 2003; Tayebi et al, 2001; Itokawa et al., 2006; Bultron et al., 2010). The new era of substrate reducing and chaperone therapies with small molecules that are able to cross the blood-brain barrier may open new perspectives in the treatment of central nervous system involvement in GD, including PD symptoms. A recent report of Hughes et al. (2007) that showed an improvement in the clinical conditions of a PD patient during SRT with

**5. Expression of GBA and other lysosomal enzyme in animal models of** 

The majority of sporadic PD cases result from interaction between genes and environment but the age remains the greatest risk factor. The first evidence of a genetic involvement in PD manifestations was the identification of three missense mutations on the α-synuclein gene, SNCA. These mutations (A30P, E46K, A53T) segregate with the disease in unrelated families and caused PD with high penetrance (Polymeropoulos et al., 1997; Kruger et al., 1998; Zarranz et al., 2004). Afterward duplication and triplication of the SNCA gene has been shown to cause PD, suggesting that high level expression of α-synuclein may also be pathogenic (Singleton et al., 2003; Ibanez et al., 2004). The degree of overexpression was found to correlate with the degree of severity of the pathology. The effects of point mutation and duplication-triplication of SNCA gene have been investigated using transgenic technology and viral infection and different mouse models were created. All PD animal models are based on the concept that parkinsonian signs are linked to dopaminergic nigral cell loss and even if they show many of the symptoms of the disease they don't display all the complexity of the neurological pathology. A lot of mouse line expressing wild-type or

average age of 57.2 years at PD onset.

weakness (16.90% vs 7.14%) in GBA carriers.

6.9±3.7, p=0.02; Herman score: 4.6±0.5 vs 2.5±1.5, p=0.002).

develop PD in GD1 patients of 21.4 (95% CI, 10.7-38.3).

Miglustat, introduces a new possible therapeutic approach.

**Parkinson's disease** 

Subsequently Aharon-Peretz et al. (2004), explored the association between six GBA mutations (N370S, L444P, c.84dupG, IVS+1A>G, R496H, V394L) and PD in Ashkenazi Jews population. From the screening of 99 patients and 1,543 healty people they identified these mutations in 31.3% of patients with PD versus 6.2% of healty controls.

Many studies have been conducted in the years, some of these have been screened PD patients for common GBA mutations (Clarck et al., 2005; Sato et al., 2005; Tan et al., 2007; Wu et al., 2007; De Marco et al., 2008; Spitz et al., 2008; Mata et al., 2008; Gan-Or et al., 2008), others have been sequenced the entire GBA gene (Eblan et al., 2006; Ziegler et al., 2007; Clark et al., 2007; Bras & Singleton, 2009; Kalinderi et al., 2009; Neumann et al., 2009).

All of these studies evidenced a higher frequency of GBA mutations among PD patients than in matched controls, but the frequency of GBA mutations varies in relation with the study's design (popolation, number and type of mutations screened or whole GBA scanning).

Toft et al. (2006) searched the association between two mutations (N370S and L444P) and PD in Norwegian population. From the analyses of 311 patients and 474 controls they found these mutations in 2.3% of subjects with PD versus 1.7% of controls.

The frequency of GBA mutations ranges between 10.7% and 31.3% in PD patients from Ashkenazi Jewish and between 2.3% and 9.4% in patients from other populations.

Most of these studies were conducted on sporadic PD patients, recently Nichols et al. (2009) and Mitsui et al. (2009) specifically investigated familial PD. They demonstrated an association between GBA variants and familial PD cases as well as sporadic disease.

Most of these studies have independently reached similar results demonstrating that GBA mutations are found in patients with PD at a higher frequency than expected.

A large meta-analysis was conducted by Sidransky et al. (2009) pooling genotypic data from 16 different centers across the world. A total of 5,691 genotyped patients with Parkinson disease and 4,898 controls were evaluated; full sequencing was performed on 1859 patient and 1674 control samples. Overall, the odds ratio for carryng a GBA mutation in subjects with PD was 5.43 (95% CI 3.89-7.57), selecting mutations in GBA gene as a common risk factor for PD.

Investigators extended their studies to analyses whether GBA mutations are related with other Lewy bodies disorders. Goker-Alpan et al. (2006), analyzing the coding region of GBA gene in 75 brain's sample of autopsy cases with pathologically confirmed Lewy body disorders, found GBA mutations in 23% of LBD patients, 4% of PD patients and none within Multiple System Atrophy patients (MSA).

Afterward Mata et al. (2008), Farrer et al. (2009) and Clark et al. (2009) showed a correlation between GBA mutations and LBD, while was found no significant difference in GBA mutations incidence between MSA patients and controls (Segarane et al., 2009).

Considering the spectrum of PD clinical manifestations in GD1 patients, a wide range of symptoms have been described, varying from the more aggressive, early-onset disease, with poor response to L-dopa therapy, to the more typical PD disease (presenting with asymmetric onset of resting tremor, bradykinesia, rigidity, gait and balance disturbance, weakness, pain, cognitive decline, and depression), responsive to L-dopa (Neudorfer et al., 1996; Tayebi et al, 2003; Bembi et al., 2003; Tayebi et al, 2001; Halperin et al. 2006; Gan-Or et al., 2008; Bultron et al., 2010; Chérin et al., 2010;). The emerging evidence of the association between GBA mutations and a variety of synucleinopathyes may account for the wide phenotype variability (Hruska at al., 2006; Velayati et al, 2010). Even if different studies described early-onset (< 50 years) as an element that characterizes this association, this observation might be influenced by the small number of patients involved in each study.

Subsequently Aharon-Peretz et al. (2004), explored the association between six GBA mutations (N370S, L444P, c.84dupG, IVS+1A>G, R496H, V394L) and PD in Ashkenazi Jews population. From the screening of 99 patients and 1,543 healty people they identified these

Many studies have been conducted in the years, some of these have been screened PD patients for common GBA mutations (Clarck et al., 2005; Sato et al., 2005; Tan et al., 2007; Wu et al., 2007; De Marco et al., 2008; Spitz et al., 2008; Mata et al., 2008; Gan-Or et al., 2008), others have been sequenced the entire GBA gene (Eblan et al., 2006; Ziegler et al., 2007; Clark et al., 2007; Bras & Singleton, 2009; Kalinderi et al., 2009; Neumann et al., 2009). All of these studies evidenced a higher frequency of GBA mutations among PD patients than in matched controls, but the frequency of GBA mutations varies in relation with the study's

Toft et al. (2006) searched the association between two mutations (N370S and L444P) and PD in Norwegian population. From the analyses of 311 patients and 474 controls they found

The frequency of GBA mutations ranges between 10.7% and 31.3% in PD patients from

Most of these studies were conducted on sporadic PD patients, recently Nichols et al. (2009) and Mitsui et al. (2009) specifically investigated familial PD. They demonstrated an

Most of these studies have independently reached similar results demonstrating that GBA

A large meta-analysis was conducted by Sidransky et al. (2009) pooling genotypic data from 16 different centers across the world. A total of 5,691 genotyped patients with Parkinson disease and 4,898 controls were evaluated; full sequencing was performed on 1859 patient and 1674 control samples. Overall, the odds ratio for carryng a GBA mutation in subjects with PD was 5.43 (95% CI 3.89-7.57), selecting mutations in GBA gene as a common risk factor for PD. Investigators extended their studies to analyses whether GBA mutations are related with other Lewy bodies disorders. Goker-Alpan et al. (2006), analyzing the coding region of GBA gene in 75 brain's sample of autopsy cases with pathologically confirmed Lewy body disorders, found GBA mutations in 23% of LBD patients, 4% of PD patients and none within

Afterward Mata et al. (2008), Farrer et al. (2009) and Clark et al. (2009) showed a correlation between GBA mutations and LBD, while was found no significant difference in GBA

Considering the spectrum of PD clinical manifestations in GD1 patients, a wide range of symptoms have been described, varying from the more aggressive, early-onset disease, with poor response to L-dopa therapy, to the more typical PD disease (presenting with asymmetric onset of resting tremor, bradykinesia, rigidity, gait and balance disturbance, weakness, pain, cognitive decline, and depression), responsive to L-dopa (Neudorfer et al., 1996; Tayebi et al, 2003; Bembi et al., 2003; Tayebi et al, 2001; Halperin et al. 2006; Gan-Or et al., 2008; Bultron et al., 2010; Chérin et al., 2010;). The emerging evidence of the association between GBA mutations and a variety of synucleinopathyes may account for the wide phenotype variability (Hruska at al., 2006; Velayati et al, 2010). Even if different studies described early-onset (< 50 years) as an element that characterizes this association, this observation might be influenced by the small number of patients involved in each study.

mutations incidence between MSA patients and controls (Segarane et al., 2009).

design (popolation, number and type of mutations screened or whole GBA scanning).

Ashkenazi Jewish and between 2.3% and 9.4% in patients from other populations.

association between GBA variants and familial PD cases as well as sporadic disease.

mutations are found in patients with PD at a higher frequency than expected.

mutations in 31.3% of patients with PD versus 6.2% of healty controls.

these mutations in 2.3% of subjects with PD versus 1.7% of controls.

Multiple System Atrophy patients (MSA).

Trying to find an answer to this issue, Gan-Or et al. (2008) performed a study analysing a large cohort of 420 unrelated Jewish Ashkenazi PD patients, which evidenced a strong correlation between GD1 and early-onset of PD symptoms (average age at onset of 51.2 years, versus 60.7 years of the noncarriers PD population), while GBA carriers showed an average age of 57.2 years at PD onset.

They also analysed the different effects of mutation severity, observing a higher risk for PD in patients carrying severe GBA mutations as well as a decreased age of symptoms onset. Finally, when they analysed clinical PD manifestations among GBA carriers and noncarriers, they observed a reduced presence of rigidity (16.90% vs 28.57%) and an increase of weakness (16.90% vs 7.14%) in GBA carriers.

Another recent large observational study of 444 consecutive GD1 patients (Bultron et al., 2010), aiming to analyse the risk of PD occurrence, showed 11 patients (2.47%) who developed the disease at a mean age of 55.0 ± 8.8 years (range 40-65 years). Analysing GD overall severe score index (SSI) and bone disease score (Hermann score) in the overall population, they found both of them significantly higher in PD patients (SSI: 10.8±0.8 vs 6.9±3.7, p=0.02; Herman score: 4.6±0.5 vs 2.5±1.5, p=0.002).

Moreover, these authors estimated age and gender-adjusted risk to develop PD in three different groups of GD1 patients, finding that the range of risk was increased 11.0 to 31.3 fold in male patients and 5.7 to 13.8 fold in female patients, with an overall relative risk to develop PD in GD1 patients of 21.4 (95% CI, 10.7-38.3).

As regard the clinical response to ERT in GD1 patients with PD, all published experiences demonstrated its effectiveness on hematological and systemic involvement, while they were ineffective in correcting PD symptoms (Neudorfer et al., 1996; Tayebi et al, 2003; Bembi et al., 2003; Tayebi et al, 2001; Itokawa et al., 2006; Bultron et al., 2010). The new era of substrate reducing and chaperone therapies with small molecules that are able to cross the blood-brain barrier may open new perspectives in the treatment of central nervous system involvement in GD, including PD symptoms. A recent report of Hughes et al. (2007) that showed an improvement in the clinical conditions of a PD patient during SRT with Miglustat, introduces a new possible therapeutic approach.
