Impact of gene mutation in the development of Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common age related neurodegenerative disorder worldwide and presents as a progressive movement disorder. Globally seven million to 10 million people have Parkinson's disease. Parkinsonism is typically sporadic in nature. Loss of dopaminergic neurons from substantia nigra pars compacta (SNpc) and the neuronal intracellular Lewy body inclusions are the major cause of PD. Gene mutation and protein aggregation play a pivotal role in the degeneration of dopamine neurons. But the actual cause of dopamine degeneration remains unknown. However, several rare familial forms of PD are associated with genetic loci, and the recognition of causal mutations has provided insight into the disease process. Yet, the molecular pathways and gene transformation that trigger neuronal susceptibility are inadequately comprehended. The discovery of a mutation in new genes has provided a basis for much of the ongoing molecular work in the PD field and testing of targeted therapeutics. Single gene mutation in a dominantly or recessively inherited gene results a great impact in the development of Parkinson's disease. In this review, we summarize the molecular genetics of PD.

The hot sites of α-synuclein in amyloid fibril formation

“…5a). The regions of (14-18), (35)(36)(37)(38)(39)(40)(41)(42), (46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57), (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80), and (90-94) were identified as chameleon sites with a high tendency for beta structure. These regions are the most likely to form the β-strands in αβT.…”

“…5c shows hydrophobicity values averaged over the sliding windows. The regions of (6-7), (16)(17), (37)(38)(39)(40), (49)(50)(51)(52)(53), (66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76), and (87-93) with values over 0 were identified as hydrophobic sites of αS. These hydrophobic regions are at the heart of hot sites and make them more potent for the formation of amyloid fibrils.…”

“…In this study, a comparison was found for monomeric αβT of αS in different conditions using TMD simulations. In the transition pathway, critical sites with a key role in the amyloid fibril formation were identified in three priorities (i) (35)(36)(37)(38)(39)(40)(41)(42)(43) and (47)(48)(49)(50)(51)(52)(53)(54)(55), (ii) (65-75), and (iii) (83-90), respectively. The regions with good overlap, as well as with aggregation-prone regions have been introduced by Pawar et al 51 .…”

The ubiquitin ligase Ariadne-1 regulates NSF for neurotransmitter release

“…The data reported here may be relevant in the context of Parkinson's disease. It should be noted that most Parkinson's related genes encode proteins involved in vesicle recycling and neurotransmitter release at the synapse (59). Thus, the kinase LRRK2 phosphorylates NSF to enhance its ATPase activity upon the SNARE complex and facilitate its disassembly (7)(8)(9).…”

Influence of Energy Deficiency on the Molecular Processes ofSubstantia Nigra Pars CompactaCell for Understanding Parkinsonian Neurodegeneration: A Comprehensive Biophysical Computational Model

“…These cellular determinants individually or collectively would result in higher basal metabolic rate and increased oxidative stress (Pacelli et al, 2015) which in turn converges to common pathologies (Duda et al, 2016) (Figure 16). At the systems level, the determinants that might contribute to differential PD phenotypes are excitotoxicity (due to overexcitation by subthalamic nucleus or pedunculopontine nucleus) (Pahapill and Lozano, 2000;Rodriguez et al, 1998), aging (due to proteostatic dysfunction, mitochondrial dysfunction, genetic mutations or telomere shortening) (Birch et al, 2018;Surmeier, 2018), genetic instability (due to changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy) (Mullin and Schapira, 2015;Selvaraj and Piramanayagam, 2019;Singleton et al, 2013), environmental toxins (due to exposure to insecticides, commercial solvents, metal exposure or traumatic head injury) (Goldman, 2014;Nandipati et al, 2016), neuroinflammation (due to traumatic head injury, exotoxins or immune dysfunctions) (Caggiu et al, 2019;Gardner et al, 2018), prion-like infection (bacteria or viruses) (Brugger et al, 2015;Caggiu et al, 2019), telomere shortening (due to aging or oxidative stress) (Kolyada et al, 2016;Scheffold et al, 2016), glial dysfunctions (due to phagocytic or inflammatory impairments, enteric glial dysfunction) (Clairembault et al, 2015;di Domenico et al, 2019;Lecours et al, 2018) and vascular dysfunctions (due to endothelial dysfunction or cardiovascular autonomic dysfunction) (Kim et al, 2017;Yang et al, 2017). These systems-level determinants interact among themselves and also across different levels in the hierarchy resulting in different PD phenotypes ( Figure 16).…”