ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B)

Abstract

Abstract-Mutation in the CHMP2B gene has been implicated in frontotemporal dementia. The authors screened CHMP2B in patients with ALS and several cohorts of control samples. They identified mutations (Q206H; I29V) in two patients with non-SOD1 ALS. Neuropathology of the Q206H case showed lower motor neuron predominant disease with ubiquitylated inclusions in motor neurons. Antibodies to p62 (sequestosome 1) showed novel oligodendroglial inclusions in the motor cortex. NEUROLOGY 2006;67:1074-1077 1 Here we show that CHMP2B (charged multivesicular body protein 2B), a gene that was recently shown to be linked to FTD, 2 was altered in two unrelated patients with ALSspectrum disorders. One mutation is predicted to alter a conserved functional domain. Pathology from this case strengthens the hypothesis of a common molecular pathology between ALS and FTD. 3 The second case showed a point substitution that has been previously described as a low-frequency variation in the CHMP2B gene. A 75-year-old man reported bulbaronset weakness for 11 months, which progressed to involve his hands after 5 months. Examination findings at that stage were a wasted, weak, fasciculating tongue, flaccid dysarthria, and bilateral weakness and wasting of the intrinsic hand muscles. Tendon reflexes were depressed, and the plantar responses were flexor. There was no evidence of significant cognitive dysfunction on bedside testing. He had a right below-knee amputation for trauma 15 years previously. Neurophysiology showed widespread neurogenic changes in bulbar, upper limb, and lower limb territories, and a diagnosis of progressive muscular atrophy (PMA) (El Escorial category of suspected ALS) was made. His weakness rapidly progressed until his death from respiratory failure 15 months after symptom onset. There was no evidence of extramotor neurologic signs or symptoms or dementia throughout the illness. A cousin was also said to have died of ALS, but it was not possible to obtain DNA from other family members.Patient 2. This 65-year-old man had behavioral and personality changes, including depression, excessive alcohol consumption, and inappropriate sexual behavior. In the next 4 years, this progressed to fulminant FTD. After 5 years, he developed motor disturbances including atrophy of the tongue and facial muscles. There was spastic dysarthria, pseudobulbar paresis causing dysphagia, and weight loss. Motor symptoms progressed to paresis of the right arm and hand and both legs. He retained normal sensation and autonomic function. There were brisk tendon reflexes and upgoing plantar responses. A diagnosis of ALS (El Escorial ALS ϩ dementia) was established on clinical and neurophysiologic grounds. Six years after the onset of behavioral symptoms, he died suddenly, but no autopsy was performed. His father was reported to have frontal lobe dysfunction and motor disturbances. This familial history was not verified by case note review, and DNA could not be obtained from other family members because of lack of permission.

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

“…The p62 protein has been found in intraneuronal or intraglial protein inclusions in a number of neurodegenerative diseases such as Alzheimer (23), Parkinson (21), and Huntington diseases (25,26). More recently, p62 was detected in intraneuronal protein aggregates in ALS with dementia patients (27), in oligodendroglial inclusions in the motor cortex of patients with ALS phenotypes caused by mutations in CHMP2B (28) and in other ALS cases (29). This study is to determine whether and how p62 may contribute to mutant SOD1 aggregation and subsequently ALS etiology.…”

“…p62 has also been found in protein aggregates in neurodegenerative disorders such as Alzheimer disease (23,24), Huntington disease (25,26), Parkinson disease (21,24) and more recently in ALS. It was found in ALS with dementia (27), in ALS caused by CHMP2B mutations (28) and in other ALS cases (29). However, the role of p62 in mutant SOD1-mediated fALS is currently undocumented.…”

Autophagy and multivesicular bodies: two closely related partners

“…[92][93][94][95] In addition, CHMP2B/Vps2B, a subunit of the ESCRT-III complex, was found to be mutated in patients with frontotemporal dementia) and amyotrophic lateral sclerosis. 96,97 Recent publications have shown that autophagy degradation is abrogated in cells depleted of ESCRT subunits or in cells overexpressing a mutant of CHMP2B that caused an accumulation of ubiquitin-protein aggregates. 35,98 Indeed, loss of mSnf7-2, a key component of ESCRT-III that is highly expressed in neurons, caused autophagosome accumulation in cortical neurons, retraction of dendrites and neuronal cell loss.…”

Roles of ESCRT in autophagy-associated neurodegeneration

“…10 Moreover, a single splice site mutation in CHMP2B, the gene encoding the human ortholog of the yeast ESCRT-III component Vps2, is mutated in a rare form of autosomal dominant frontotemporal dementia (FTD3) and amyotrophic lateral sclerosis (ALS). [11][12][13] However, detailed molecular mechanisms of neurodegeneration associated with FTD remain unknown.…”