Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

Abstract

Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin‐related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1‐dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid β (Aβ) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1‐associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with Aβ, phosphorylated τ, and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.

Drp1 is widely, yet heterogeneously, distributed in the mouse central nervous system

“…It has been confirmed that many diseases are related to Drp1 and mitochondria, including neurodegenerative diseases and neuropathic pain [12]. Gao et al have demonstrated that mitochondrial dysfunction is a common prominent early pathological feature in neurodegenerative diseases [13].…”

Do You Remember Mitochondria?

“…Fusion of the outer mitochondrial membrane (OMM) is mainly dependent on the GTPase Mitofusin 1 and 2 (Mfn-1 and -2) (Eura et al, 2003); whilst fusion of the inner mitochondrial membrane occurs thanks to the activity of the dynamin-related GTPase Optic-Athropy-1 (Opa-1) protein (Cipolat et al, 2004). Fission of the mitochondrial network occurs through the activity of the GTPase Dynamin-Related-Protein-1 (Drp1) (Oliver and Reddy, 2019;Qi et al, 2019). After an initial constriction of the OMM, due to the interaction with the endoplasmic reticulum and actin filaments, Drp-1 forms multimeric spirals around the OMM, which further constrict until they divide the membranes, using GTP hydrolysis FIGURE 2 | Mitochondrial dynamics depends on the balance of Fission and Fusion processes.…”

Drp1 widely, yet heterogeneously distributes in mice central nervous system

“…It has been confirmed that many diseases are related with Drp1 and mitochondria, including neurodegenerative diseases and neuropathic pain [12]. Ju Gao et al revealed that mitochondrial dysfunction has been demonstrated as a common prominent early pathological feature in neurodegenerative diseases [13].…”