Dysfunctional mitochondria uphold calpain activation: contribution to Parkinson's disease pathology.
Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic neuronal function. However, mitochondrial-mediated-calcium homeostasis alterations may lead to its pathologic activation that jeopardizes neuronal structure and function. Here, we provide evidence to support a role for the involvement of calpain 1 in mitochondrial-induced neurodegeneration in a Parkinson's disease (PD) cellular model. We show that dysfunctional mitochondria increases cytosolic calcium, thereby, inducing calpain activation. Interestingly, its inhibition significantly attenuated the accumulation of alpha-synuclein oligomers and contributed to an increase of insoluble alpha-synuclein aggregates, known to be cytoprotective. Moreover, our data corroborate that calpain-1 overactivation in our mitochondrial-deficient cells promote caspase-3 activation. Overall, our findings further clarify the crucial role of dysfunctional mitochondria in the control of molecular mechanisms occurring in PD brain cells, providing a potentially novel correlation between the degradation of calpain substrates suggesting a putative role of calpain and calpain inhibition as a therapeutic tool in PD.
Esteves
A Raquel
AR
Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3004-Coimbra, Portugal.
Arduíno
Daniela M
DM
Swerdlow
Russell H
RH
Oliveira
Catarina R
CR
Cardoso
Sandra M
SM
D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000503:physiopathology; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D051844:alpha-Synuclein / Q000378:metabolism
D051844:alpha-Synuclein; D002154:Calpain; D053148:Caspase 3; D002118:Calcium