Elucidating Critical Proteinopathic Mechanisms and Potential Drug Targets in Neurodegeneration

Abstract

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.

Keywords: Chaperones; Drug targets; Free radicals; Mitophagy; Neurodegeneration.

Fig. 1

Structures of drugs/molecules currently employed for the treatment of neurodegenerative diseases or being tested in clinical trials

Fig. 1

Structures of drugs/molecules currently employed for the treatment of neurodegenerative diseases or being tested in clinical trials

Fig. 2

Diverse proteins found deregulated during neurodegenerative diseases and the associated common pathological symptoms

Fig. 3

Amyloidogenic pathway of Alzheimer’s disease: Beta secretase cleaves Amyloid precursor protein into soluble amyloid precursor protein-beta (APP-β) and C99 fragment. The later in the presence of gamma secretase cleaves to amyloid beta and AICD fragment. Amyloid beta Aβ undergoes oligomerization and plaque formation leading to inflammation, oxidative stress and finally neuronal death

Fig. 4

Demonstration of N-APP-DR6-Caspase-6 pathway of Alzheimer’s disease AD. Beta secretase cleaves amyloid precursor protein (APP), generating two fragments. Then some unknown enzyme cleaves one of the fragments towards N terminal of APP to generate N- terminal fragment amyloid precursor protein known as N-APP fragment. The later binds to death receptor-6 (DR6) located in the neuronal membrane. N-APP/DR6 interaction triggers the apoptotic pathway by activating caspase-6 that causes neuronal death leading to Alzheimer’s disease

Fig. 5

Non-amyloidogenic pathway of Alzheimer’s disease: Alpha secretase cleaves APP to generate the neuroprotective fragment _SAPP_α towards N terminal via ectodomain shedding. The other remaining fragment of APP fragment is cleaved by gamma secretase into two subfragments P3 and amino-terminal APP intracellular domain (AICD)

Fig. 6

Prolonged activation of acetylcholine esterase caused decline of acetylcholine (neurotransmitter). The strategy to inhibit acetylcholinesterase using acetylcholinesterase inhibitors is looked as a promising approach to raise the level of acetylcholine and promote continued stimulation of the muscles and glands

Fig. 7

Glutamate induced activation of NMDAR, calcium influx, free radical generation and subsequent neuronal death

Fig. 8

Pathophysiology of Parkinsonism and its cardinal signs

Fig. 9

Figure depicting the altered/mutated parkin affects normal ubiquitination process thereby inhibiting the proteasome-mediated breakdown of selected proteins. Accumulation of the latter causes neurotoxicity and hence neurodegeneration

Fig. 10

Pathophysiology of Creutzfeldt Jakob disease (CJD): Factors like mutations in prion gene, infections of nervous tissue and heredity transmission of infected prions can change the normal prion to infected/misfolded prion. Accumulation of infected/misfolded prion in the brain causes neurodegeneration characterised by spongiform brain with clinical manifestations like paranoia, dementia and obsessive compulsiveness

Fig. 11

Proteinopathy triggered mitochondrial complex deficiencies during neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Alzheimer’s disease (AD) and Parkinson’s disease (PD)

Fig. 12

Oxidative stress, free radical generation and neuronal damage