Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration...

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GRD Journals- Global Research and Development Journal for Engineering | Volume 6 | Issue 6 | May 2021 ISSN- 2455-5703

Accumulation of Alpha-Synuclein Aggregates and it's Causes, Eventually Lead to Neurodegeneration Resulting into Pathogenesis of Parkinson's Disease Janhavi Dhore Student Department of Biological & Bio System Engineering Ajeenkya DY Patil University, Pune

Abstract Parkinson's disease (PD) is the second most common neurodegenerative (ND) disorder known to occur all over the world, mostly in the old-aged people. PD is recognised as an α-Synucleinopathy which features the accumulation of ND protein that is alphasynuclein (α-syn), in neuronal and glial cells. It is acquainted with poor neuronal signalling and impaired neurons mainly in the substantia nigra part of the central nervous system. Aggregates of α-synuclein were discovered to be the building blocks of Lewy Bodies(LB), which is the pathological hallmark of PD. Lewy pathology accumulation resulted in progressive loss of dopaminergic neurons in the substantia nigra pars compacta. On the other hand, astrocytes are major and most abundant glial cell type in the brain, which are found to degrade α-syn to some extent. They can transfer the protein from one neuron to other directly or through Tunneling nanotubes (TNTs). However, due to over accumulation, over longer period of time it results into mitochondrial abnormalities and detrimental cellular processes in astrocytes therefore leading to glial cell death. The abnormal ND protein accumulation is identified to be caused due to a range of external and internal factors which dysrupts the intracellular and extracellular activities of neuronal cells. Specifically, α-syn aggregates might have been triggered by various factors such as: aging, environmental-oxidative stress or inflammation, genetic mutations and polymorphisms, impaired cellular processes like protein clearance systems (UPS and ALP) and dysfunction of mitochondrial and lysosomal pathways. α-Syn portrays a vicious cycle wherein damage to proteasomal and lysosomal systems could cause α-Syn to accumulate, and thereby increased levels of α-Syn could inhibit the proteasome and lysosomal systems, ultimately leading to the formation of oligomers and aggregates, which results into neurodegeneration and clinical dysfunction. It causes mitochondrial and lysosomal dysfunction which eventually leads to cell death and neurodegeneration leading to PD pathogenesis. Keywords- Parkinson's Disease, Alpha-Synuclein, Lewy Body, Astrocytes, Neurodegeneration, Mitochondrial Dysfunction, Lysosomal Dysfunction

I. INTRODUCTION Studies delineate that diverse neurodegenerative (ND) disorders comprising of Parkinson's disease (PD), Alzheimer's disease (AD), Huntington’s and prion diseases, frontotemporal dementia and motor neuron diseases which are considered to be caused due to accumulation and deposition of various misfolded, abnormal aggregates of protein like amyloid-ß, tau, alpha-synuclein (α-syn). [1], [2] The deposition of aberrant protein results into malfunctioning of neurons since it triggers mitochondrial dysfunction, disruption of autophagy and endo-lysosomal pathways which in turn leads to degeneration of dopaminergic neurons in the substantia nigra which advances towards the pathogenesis of PD. [1], [3], [4] Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death. [5] Recapitulation of a ND cascade thus establishes a mechanistic link between transmission of pathologic α-syn and the cardinal features of PD.[6] A. Parkinson's Disease (PD) PD is the second most common neurodegenerative disorder known to occur all over the world, mostly in the old-aged people. [3] PD is an α-Synucleinopathy which features the accumulation of aggregated α-syn in neuronal and glial cells. [7], [8] PD is marked with symptoms such as tremors and weakness. The tremors occurring when a patient at rest had accompanying features of movement rigidity, slowed movements, a typical hunched posture, and very soft speech whereas a patient in action showed signs of weakness spasticity, and visual disturbance.[9] Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity, along with non-motoric symptoms like autonomic, cognitive, and psychiatric problems.[10] Moreover, clinical symptoms of PD demonstrate dysfunction of synapses as All rights reserved by www.grdjournals.com

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