Elucidating Critical Proteinopathic Mechanisms and Potential Drug Targets in Neurodegeneration

• Published in: Cellular and molecular neurobiology 2020-04, Vol.40 (3), p.313-345
• Main Authors: Dar, Khalid Bashir, Bhat, Aashiq Hussain, Amin, Shajrul, Reshi, Bilal Ahmad, Zargar, Mohammad Afzal, Masood, Akbar, Ganie, Showkat Ahmad
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (muscarinic); Acetylcholinesterase; Adenosine A2A receptors; Aging; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Animals; Anxiety; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Cell Biology; Chaperones; Cognitive ability; Creutzfeldt-Jakob disease; Creutzfeldt-Jakob Syndrome - metabolism; Creutzfeldt-Jakob Syndrome - pathology; Creutzfeldt-Jakob Syndrome - physiopathology; Deregulation; Emotional behavior; Glial cell line-derived neurotrophic factor; Glutamic acid receptors; Humans; Leucine; Lewy bodies; LRRK2 protein; Mitochondria; Molecular Targeted Therapy - methods; Molecular Targeted Therapy - trends; Mood; N-Methyl-D-aspartic acid receptors; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neuronal-glial interactions; Neurosciences; Oligomerization; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Prion protein; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - physiopathology; Protein Aggregation, Pathological - therapy; Proteome - analysis; Proteome - metabolism; Proteomics; Review Paper; Secretase; Signal Transduction - physiology; Synuclein; Therapeutic targets
• ISSN: 0272-4340; 1573-6830; 1573-6830
• DOI: 10.1007/s10571-019-00741-0

Neurodegeneration entails progressive loss of neuronal structure as well as function leading to cognitive failure, apathy, anxiety, irregular body movements, mood swing and ageing. Proteomic dysregulation is considered the key factor for neurodegeneration. Mechanisms involving deregulated processing of proteins such as amyloid beta (Aβ) oligomerization; tau hyperphosphorylation, prion misfolding; α-synuclein accumulation/lewy body formation, chaperone deregulation, acetylcholine depletion, adenosine 2A (A2A) receptor hyperactivation, secretase deregulation, leucine-rich repeat kinase 2 (LRRK2) mutation and mitochondrial proteinopathies have deeper implications in neurodegenerative disorders. Better understanding of such pathological mechanisms is pivotal for exploring crucial drug targets. Herein, we provide a comprehensive outlook about the diverse proteomic irregularities in Alzheimer’s, Parkinson’s and Creutzfeldt Jakob disease (CJD). We explicate the role of key neuroproteomic drug targets notably Aβ, tau, alpha synuclein, prions, secretases, acetylcholinesterase (AchE), LRRK2, molecular chaperones, A2A receptors, muscarinic acetylcholine receptors (mAchR), N-methyl-D-aspartate receptor (NMDAR), glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and mitochondrial/oxidative stress-related proteins for combating neurodegeneration and associated cognitive and motor impairment. Cross talk between amyloidopathy, synucleinopathy, tauopathy and several other proteinopathies pinpoints the need to develop safe therapeutics with ability to strike multiple targets in the aetiology of the neurodegenerative disorders. Therapeutics like microtubule stabilisers, chaperones, kinase inhibitors, anti-aggregation agents and antibodies could serve promising regimens for treating neurodegeneration. However, drugs should be target specific, safe and able to penetrate blood–brain barrier.