Dynamin‐2 in nervous system disorders

Abstract

Dynamin-2 is a pleiotropic GTPase whose best-known function is related to membrane scission during vesicle budding from the plasma or Golgi membranes. In the nervous system, dynamin-2 participates in synaptic vesicle recycling, postsynaptic receptor internalization, neurosecretion, and neuronal process extension. Some of these functions are shared with the other two dynamin isoforms. However, the involvement of dynamin-2 in neurological illnesses points to a critical function of this isoform in the nervous system. In this regard, mutations in the dynamin-2 gene results in two congenital neuromuscular disorders. One of them, Charcot-Marie-Tooth disease, affects myelination and peripheral nerve conduction, whereas the other, Centronuclear Myopathy, is characterized by a progressive and generalized atrophy of skeletal muscles, yet it is also associated with abnormalities in the nervous system. Furthermore, single nucleotide polymorphisms located in the dynamin-2 gene have been associated with sporadic Alzheimer's disease. In the present review, we discuss the pathogenic mechanisms implicated in these neurological disorders.

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

“…Human mutations in DRP1 or DYN2 have been associated with neurological impairments (Gonzalez-Jamett et al, 2014; Vanstone et al, 2016; Waterham et al, 2007). Drp1, despite lacking a transmembrane domain, cycles from the cytosol to spots on the mitochondrial outer membrane (Smirnova et al, 1998) by interacting with several proteins, including Fis1, Mff, MiD49, MiD51 and a BAR-domain protein endophilin B1 (Cerveny et al, 2001; Cherok et al, 2017; Fekkes et al, 2000; Gandre-Babbe and van der Bliek, 2008; Otera et al, 2010; Palmer et al, 2011; Tieu and Nunnari, 2000; Zhao et al, 2011).…”

Expression of a dynamin 2 mutant associated with Charcot-Marie-Tooth disease leads to aberrant actin dynamics and lamellipodia formation

“…Eight CMT-associated mutations in dynamin 2 have been reported to date [9]. These mutations occur mainly at the PH domain, which is the binding motif for phosphoinositide binding.…”

“…These mutations occur mainly at the PH domain, which is the binding motif for phosphoinositide binding. Mutations have also been detected in the middle and PRD domains [9]. Analysis of fibroblasts derived from CMT patients or cells expressing CMT mutant dynamin 2 showed that mutations in the PH domain lead to defective endocytosis of surface receptors, including EGF and transferrin receptors [10,11].…”

Clinical Reasoning: A 51-year-old woman with weakness and stiff neck

“…7 Dynamin-2 is one of 3 isoforms of dynamin, and acts as a GTPase involved in endocytosis and membrane remodeling. 12,13 Their major role is in membrane fission, but there is an expanding number of functions attributed to the dynamin proteins, such as microtubule and cytoskeletal maintenance, transportation of molecules from organelles like the Golgi apparatus, and calcium homeostasis. 11,12 Mutations in DNM2 can also cause intermediate and axonal dominant forms of Charcot-Marie-Tooth neuropathy (CMT).…”

“…12,13 Their major role is in membrane fission, but there is an expanding number of functions attributed to the dynamin proteins, such as microtubule and cytoskeletal maintenance, transportation of molecules from organelles like the Golgi apparatus, and calcium homeostasis. 11,12 Mutations in DNM2 can also cause intermediate and axonal dominant forms of Charcot-Marie-Tooth neuropathy (CMT). The mutations associated with CNM tend to occur in different locations within the DNM2 gene than those associated with CMT.…”