Dynamin‐like protein 1 cleavage by calpain in Alzheimer’s disease

Abstract

Abnormal mitochondrial dynamics contributes to mitochondrial dysfunction in Alzheimer's disease (AD), yet the underlying mechanism remains elusive. In the current study, we reported that DLP1, the key mitochondrial fission GTPase, is a substrate of calpain which produced specific N‐terminal DLP1 cleavage fragments. In addition, various AD‐related insults such as exposure to glutamate, soluble amyloid‐β oligomers, or reagents inducing tau hyperphosphorylation (i.e., okadaic acid) led to calpain‐dependent cleavage of DLP1 in primary cortical neurons. DLP1 cleavage fragments were found in cortical neurons of CRND8 APP transgenic mice which can be inhibited by calpeptin, a potent small molecule inhibitor of calpain. Importantly, these N‐terminal DLP1 fragments were also present in the human brains, and the levels of both full‐length and N‐terminal fragments of DLP1 and the full‐length and calpain‐specific cleavage product of spectrin were significantly reduced in AD brains along with significantly increased calpain. These results suggest that calpain‐dependent cleavage is at least one of the posttranscriptional mechanisms that contribute to the dysregulation of mitochondrial dynamics in AD.

Calpains play an essential role in mechanical ventilation-induced diaphragmatic weakness and mitochondrial dysfunction

“…In this regard, calpain-mediated cleavage of PKC-δ results in a catalytically active fragment that appears at a molecular weight of ~45 kDa [ 34 , 35 ]. In addition, calpains cleave DRP1 generating a DRP1 cleavage fragment that appears at ~50 kDa [ 36 ]. CAST overexpression prevented the MV-induced increase in PKC-δ and DRP1 cleavage fragments.…”

“…Our results also provide evidence of accumulation of a DRP1 cleavage fragment in diaphragm fibers during MV. Although the physiological relevance of this DRP1 cleavage protein remains unclear, recent evidence indicates that cleavage of DRP1 by calpains contributes to mitochondrial dysfunction in Alzheimer's disease [ 36 ]. In this regard, disruptions in the balance of mitochondrial fission and fusion have been shown to result in mitochondrial dysfunction and promote muscle atrophy [ 56 , 57 ].…”

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

“…Indeed, biochemical evaluation of AD brains demonstrated significantly reduced protein expression levels of all the large dynamin-related GTPases involved in fission and fusion including DLP1, OPA1, Mfn1, and Mfn2 along with significantly increased levels of fission factor, Fis1, in AD brain [101,105]. Given that DLP1 and Mfn2 are substrates of calpain and cleaved by calpain activation induced by multiple AD-relevant insults in vitro [106], the fact that reduced levels of these GTPases correlated with calpain activation in AD brain suggests that calpain-mediated degradation could at least contribute to the reduction of these fission/fusion GTPases in AD [106]. Despite some controversial reports on the expression of DLP1 in the AD brain [105], studies from multiple groups demonstrated significant changes in the post-translational modifications of DLP1 consistent with its increased translocation to mitochondria in AD: Cho et al reported that Aβ induced S-nitrosylation of DLP1 (forming SNO-Drp1) triggered mitochondrial fission, synaptic loss, and neuronal damage in AD [107].…”

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

“…The fission-related protein DLP1 is reported to be associated with refractory epilepsy and neonatal lethality [13], while Mff is linked to developmental delay with neuromuscular dysfunction [14]. Interestingly, studies from multiple groups demonstrated fragmented mitochondria in cell models and animal models of AD, as well as in the pyramidal neurons in the brains of human AD patients [15][16][17][18][19][20][21][22]. Consistently, decreased mitochondria fusion proteins including OPA1, Mfn1, and Mfn2, along with increased fission proteins such as Fis1 and DLP1, are found in the AD brain and models of AD, which suggests that impaired fusion and/or enhanced fission is likely involved [21][22][23].…”