**7. Metabolic dysfunction and its link to Parkinson's disease (PD): The role of dehydrogenases**

PD is a neurological disorder characterized by typical motor features such as tremor bradykinesia, rigidity, slowness of movement and postural instability. Reduction in number of dopaminergic (DA) neurons located in substantia nigra pars compacta is the pathological cause of PD. It is also characterized by accumulation of α-synuclein into inclusions called Lewy bodies. 60% of DA neurons are dead and 70% responsiveness of DA is lost. Mostly PD is idiopathic, however specific genetic mutations have shown to increase the risk to develop PD. Mutations is genes such as α-synuclein, Parkin, PINK1 have been reported so far. After diagnosis of PD based on its classical symptoms and neuroimaging, treatment is usually done using levodopa (L-DOPA). L-DOPA is converted to dopamine in the brain and can temporarily alleviate the motor symptoms. Dopamine receptor agonists as well as selective monoamine oxidase-B (MAO-B) inhibitors are also administered along with L-DOPA (97;98). Treatment thus helps to partially reduce the symptoms of PD, since the actual underlying cause of this disease is still unknown. Altered enzyme activity and mitochondrial dysfunction has been linked to PD as well.

106 Dehydrogenases

Down's syndrome.

**role of dehydrogenases** 

In another study, ABAD-decoy peptide (ABAD-DP) was introduced in the Tg mAPP mice, which prevented the interaction of ABAD with Aβ. As expected, reduction in ABAD-Aβ complex formation accompanied with attenuated oxidative stress, increased oxygen consumption, increased activity of enzymes associated with mitochondrial respiratory chain, improvement in energy metabolism, and increased spatial memory (89). Thus based on these studies, inhibitors of ABAD-Aβ hold promise as potential targets for the treatment of AD.

Another dehydrogenase that is implicated in AD progression is aldehyde dehydrogenase (ALDH) (89;94). Aldehyde dehydrogenase is observed as a key enzyme in the brain involved in metabolism and degradation of biogenic aldehydes, monoamine neurotransmitters such as norepinephrine, dopamine, diamines and GABA. Recent studies have also shown that patients with Down's syndrome have reduced activity of ALDH enzyme (95). Two dimensional analysis of proteins extracted from brain samples of nine aged patients with Down's syndrome and nine controls showed that ALDH was down regulated in the patients with Down's syndrome. This resulted in accumulation of aldehydes and further formation of tangles and plaques as observed in aged patients with

Oxidative stress and generation of ROS species has been implicated in Alzheimer's disease as elaborated earlier. These oxygen species modify proteins, nucleic acids as well as lead to lipid peroxidation. Lipid peroxidation produces toxic aldehydes such as 4-hydroxy-2-nonenal (HNE) in several disorders such as Alzheimer's as well as Parkinson's disease. In the brain, normally ALDH2- an isoform of aldehyde dehydrogenase oxidizes and degrades end product of lipid peroxidation such as HNE. The role of ALDH in oxidative stress and age dependent memory loss and decline in cognitive function was studied using a transgenic mouse model with defective ALDH2 (96). A dominant negative form of ALDH2 mice was produced and its effect on the metabolic pathways as well as accumulation of toxic products was tested. As expected HNE accumulation was observed in such transgenic mice compared to controls. Further testing of cognitive capability was performed using object recognition and water maze test. Decreased cognitive function in the transgenic mice was observed along with accumulation of tau phosphorylation (a typical pathological sign of Alzheimer's disease).

A dominant negative form of ALDH2 mice was produced and its effect on the metabolic pathways as well as accumulation of toxic products was tested. As expected HNE accumulation was observed in such transgenic mice compared to controls. Further testing of cognitive capability was performed using object recognition and water maze test. Decreased cognitive function in the transgenic mice was observed along with accumulation of tau

**7. Metabolic dysfunction and its link to Parkinson's disease (PD): The** 

PD is a neurological disorder characterized by typical motor features such as tremor bradykinesia, rigidity, slowness of movement and postural instability. Reduction in number of dopaminergic (DA) neurons located in substantia nigra pars compacta is the pathological

phosphorylation (a typical pathological sign of Alzheimer's disease).

Aldehyde dehydrogenase plays an important role in detoxifying aldehydes in brain. Reduced expression of isoforms of ALDH such as ALDH1A1 and ALDH2 is reported in PD patients. In addition impaired Complex I activity is documented in PD which can reduce the availability of NAD+ cofactor required by ALDHs to remove toxic biogenic aldehydes. Thus decreased ALDH function could be the underlying factor preceding the development of PD. Using transgenic mice null for both ALDH1A1 and ALDH2, the risk to develop PD was tested (99). Such mice exhibited deficits in motor performance typical of PD. Loss of DA with increased accumulation of biogenic aldehydes such as HNE was observed. L-DOPA administration alleviated the motor deficits suggesting a role of ALDHs in the pathophysiology of PD.

Another DHO implicated in PD is glutamate dehydrogenase (GDH). GDH is a key enzyme involved in interconversion of glutamate to alpha-ketoglutarate and ammonia using NADP(H) and NAD(H) as co factors. It plays an important role in homeostasis by interconnecting amino acid and carbohydrate metabolism pathways. Present in two isoforms in humans, the GDH isoform 2 (hGDH2) is overexpressed in the brain astrocytes and the sertoli cells in testis. ADP levels act as positive regulators for this enzyme and unlike the other isoform it is not inhibited by GTP. Important in recycling glutamate in the brain astrocytes, this enzyme works in concert with glutamine synthetase (GS) providing ammonia as well as ATP for GS activity. Two parallel studies have shown that increased levels of glutamate prepones the onset of the disease by 6 to 13 years (100). Hemizygous individuals with a rare variation in hGDH2 (substitution of Ala for Ser445) was detected in these individuals. GDH deficiencies have also been linked to the onset of epilepsy. All together these results highlight the role of hGDH2 in the maintenance of brain homeostasis.

ABAD associated with Alzheimer's disease has also shown to play some role in PD disease. ABAD expression is seen to be downregulated in PD patients (101). In mouse models of PD generated by administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ABAD expression is significantly reduced. By contrast, overexpression of ABAD in transgenic mice is shown to attenuate MPTP-induced dopaminergic neurogeneration. This strongly suggests that ABAD may contribute to the fate of DA neurons during the onset of PD.
