神经系统疾病

An Attempt to Unearth the Chemical and Molecular Mechanisms behind Causation of Parkinson′s Disease After Two Centuries Since its First Description

Abstract

Nagalakshmi CS, Santhosh NU , RG Varma , Lokesh B , Mirza MA , Anuradha HK

Parkinson′s disease (PD) is an age-related neurodegenerative disorder that affects approximately 1 million persons in the United States. It is characterized by resting tremor, rigidity, bradykinesia, gait disturbance and postural instability. Its pathological features include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intra-cytoplasmic inclusions known as Lewy bodies. Neuro-degeneration and Lewy bodies can also be found in locus ceruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of autonomic nervous system. The appearance of Lewy-body-like inclusions in nigro-striatal terminals might be followed by retrograde degeneration, further accumulation of aggregated proteins in nigral cell bodies and, finally, reactive gliosis and cell death. In familial forms of Parkinson′s disease, linked to mutations in α-synuclein, it is proposed that a loss of normal function of this protein, as well as a toxic effect of altered forms of the mutant protein, promote the accumulation of dopamine in cytoplasm. This would result in oxidative stress, leading to the onset of neurodegenerative changes mentioned above. Finally, we review evidence for a role of α-synuclein in synaptic vesicle recycling and suggest that impaired function of this protein might lead to accumulation of dopamine in cytoplasm. This could be the final deleterious event that triggers the death of nigral dopaminergic neurons in PD.