Calpain in the cleavage of alpha-synuclein and the pathogenesis of Parkinson's disease

Shams, Ramsha; Banik, Naren L.; Haque, Azizul

doi:10.1016/bs.pmbts.2019.06.007

Cited by 18 publications

(12 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…α-Syn truncations originate from incomplete degradation, which has been attributed to various cytosolic ( 13 – 15 ) and lysosomal proteases ( 16 , 17 ). In fact, ∼60% of the abovementioned truncations can be assigned to cleavages by lysosomal asparagine endopeptidase (AEP), cathepsin (Cts) D, CtsB, and CtsL ( 15 – 17 ).…”

mentioning

confidence: 99%

The N terminus of α-synuclein dictates fibril formation

McGlinchey

Shadish

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The generation of α-synuclein (α-syn) truncations from incomplete proteolysis plays a significant role in the pathogenesis of Parkinson’s disease. It is well established that C-terminal truncations exhibit accelerated aggregation and serve as potent seeds in fibril propagation. In contrast, mechanistic understanding of N-terminal truncations remains ill defined. Previously, we found that disease-related C-terminal truncations resulted in increased fibrillar twist, accompanied by modest conformational changes in a more compact core, suggesting that the N-terminal region could be dictating fibril structure. Here, we examined three N-terminal truncations, in which deletions of 13-, 35-, and 40-residues in the N terminus modulated both aggregation kinetics and fibril morphologies. Cross-seeding experiments showed that out of the three variants, only ΔN13-α-syn (14‒140) fibrils were capable of accelerating full-length fibril formation, albeit slower than self-seeding. Interestingly, the reversed cross-seeding reactions with full-length seeds efficiently promoted all but ΔN40-α-syn (41–140). This behavior can be explained by the unique fibril structure that is adopted by 41–140 with two asymmetric protofilaments, which was determined by cryogenic electron microscopy. One protofilament resembles the previously characterized bent β-arch kernel, comprised of residues E46‒K96, whereas in the other protofilament, fewer residues (E61‒D98) are found, adopting an extended β-hairpin conformation that does not resemble other reported structures. An interfilament interface exists between residues K60‒F94 and Q62‒I88 with an intermolecular salt bridge between K80 and E83. Together, these results demonstrate a vital role for the N-terminal residues in α-syn fibril formation and structure, offering insights into the interplay of α-syn and its truncations.

show abstract

mentioning

confidence: 99%

The N terminus of α-synuclein dictates fibril formation

McGlinchey

Shadish

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Histological evaluations of neurons taken from postmortem PD samples and MPTP-treated lesioned rats likewise reveal gliosis, neurofibrillary tangles, and LB formation in both the SN and SC [3,21,42]. In healthy individuals, α-syn proteins are primarily located in the CNS and comprise 10% of cytosolic protein [43]. In PD patients, however, α-syn proteins mutate and truncate, leading to harmful aggregation.…”

Section: Lb and α-Syn Aggregation In Pdmentioning

confidence: 99%

“…In healthy individuals, α -syn proteins are primarily located in the CNS and comprise 10% of cytosolic protein [ 43 ]. In PD patients, however, α -syn proteins mutate and truncate, leading to harmful aggregation.…”

Section: Lb and α -Syn Aggregation In Pdmentioning

confidence: 99%

“…Maintaining Ca 2+ homeostasis is vital for regulating many signaling pathways and biological systems in the body [ 43 ]. Among other roles, Ca 2+ serves as a physiological messenger for transport across the plasma membrane and enzymatic activation [ 65 ].…”

Section: Dysregulation Of Ca 2+ Homeostasis In Pdmentioning

confidence: 99%

“…Ca 2+ is unique from other signaling ions, such as Na+ and K+, as the concentration is 20,000-fold lower in the cytoplasm compared to the extracellular space (significantly less than the ~10- to 30-fold difference for Na+ and K+ ion concentrations). As a result of the extreme concentration gradient, Ca 2+ acts as a potent intracellular signaling ion, responding rapidly to changes in extracellular and intracellular environments [ 43 ]. Thus, controlling Ca 2+ movement enables a wide range of physiological functions through the activation and inhibition of Ca 2+ -dependent signals.…”

Section: Dysregulation Of Ca 2+ Homeostasis In Pdmentioning

confidence: 99%

See 2 more Smart Citations

Calpain activation and progression of inflammatory cycles in Parkinson’s disease

Gao¹,

McCoy²,

Zaman³

et al. 2022

Front. Biosci. (Landmark Ed)

Self Cite

View full text Add to dashboard Cite

Parkinson's disease (PD) is a progressive, neurodegenerative condition of the central nervous system (CNS) affecting 6.3 million people worldwide with no curative treatments. Current therapies aim to mitigate PD's effects and offer symptomatic relief for patients. Multiple pathways are involved in the pathogenesis of PD, leading to neuroinflammation and the destruction of dopaminergic neurons in the CNS. This review focuses on PD pathology and the role of calpain, a neutral protease, as a regulator of various immune cells such as T-cells, microglia and astrocytes which lead to persistent neuroinflammatory responses and neuronal loss in both the brain and spinal cord (SC). Calpain plays a significant role in the cleavage and aggregation of toxic α-synuclein (α-syn), a presynaptic neural protein, and other organelles, contributing to mitochondrial dysfunction and oxidative stress. α-Syn aggregation results in the formation of Lewy bodies (LB) that further contribute to neuronal damage through lipid bilayer penetration, calcium ion (Ca 2+ ) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca 2+ concentrations, raising intracellular Ca 2+ ; this leads to excessive calpain activation and persistent inflammatory responses. α-Syn aggregation also results in the disruption of dopamine synthesis through phosphorylation of tyrosine hydroxylase (TH), a key enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), the amino acid precursor to dopamine. Decreased dopamine levels result in altered dopamine receptor (DR) signaling, ultimately activating pro-inflammatory T-cells to further contribute to the inflammatory response. All of these processes, together, result in neuroinflammation, degeneration and ultimately neuronal death seen in PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+)), rotenone (an environmental neurotoxin), and 6-hydroxydopamine (6-OHDA -a neurotoxic synthetic organic compound) induce PD-like conditions when injected into rodents. All three agents work through similar mechanisms and lead to degeneration of dopaminergic neurons in the substantia nigra (SN) and more recently discovered in motor neurons of the spinal cord (SC). These neurotoxins also increase calpain activity, furthering the neuroinflammatory response. Hence, calpain inhibitors have been posited as potential therapeutics for PD to prevent calpain-related inflammation and neurodegenerative responses in not only the SN but the SC as well.

show abstract

The Ca2+-Regulated Enzymes Calpain and Calcineurin in Neurodegenerative Processes and Prospects for Neuroprotective Pharmacotherapy

Knaryan,

Sarukhanyan

2024

Neurosci Behav Physi

View full text Add to dashboard Cite

Calpain in the cleavage of alpha-synuclein and the pathogenesis of Parkinson's disease

Cited by 18 publications

References 79 publications

The N terminus of α-synuclein dictates fibril formation

The N terminus of α-synuclein dictates fibril formation

Calpain activation and progression of inflammatory cycles in Parkinson’s disease

The Ca2+-Regulated Enzymes Calpain and Calcineurin in Neurodegenerative Processes and Prospects for Neuroprotective Pharmacotherapy

Contact Info

Product

Resources

About