Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia
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Abstract:
Ubiquilin-2 (UBQLN2) is a member of the ubiquilin family, actively implicated in the degradation of misfolded and redundant proteins through the ubiquitin-proteasome system and macroautophagy. UBQLN2 received much attention after the discovery of gene mutations in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The abnormal presence of positive UBQLN2 inclusion in the cytosol of degenerating motor neurons of familial and sporadic forms of ALS patients has been newly related to neurodegeneration. Only recently, data have emerged on its role in liquid-liquid phase separation, in stress granule development and in the formation of secondary amyloid structures. Furthermore, several animal models are available to investigate its involvement in TDP-43 pathology and neuroinflammation in ALS. This review addresses the molecular pathogenetic pathways involving UBQLN2 abnormalities which are converging toward defects in clearance mechanisms. UBQLN2.Keywords:
Stress granule
Frontotemporal lobar degeneration
Frontotemporal lobar degeneration
Semantic dementia
Nosology
Corticobasal degeneration
Neuropsychiatry
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Objective: To review the phenotype of patients with ALS and FTD/ALS in c9FTD/ALS. Background A hexanucleotide repeat expansion in C9ORF72 recently reported as a major cause of familial ALS, FTD/ALS and FTD, designated c9FTD/ALS, also was found in sporadic ALS and FTD patients (doi:10.1016/j.neuron.2011.09.010; doi:10.1016/j.neuron.2011.09.011). Few data regarding the c9FTD/ALS phenotype in ALS and FTD/ALS are available. Design/Methods: 231 patients with ALS or FTD/ALS identified at the Mayo Clinic Florida ALS Center were screened for the c9FTD/ALS mutation. Patients completed a standard ALS diagnostic evaluation including EMG, and neuropsychological testing where indicated. Autopsy was performed in 5 mutation carriers. Results: Eighteen patients (15 ALS (9 male); 3 FTD/ALS (1 male; cognitive dysfunction preceded ALS in 2) representing 17 independent pedigrees had a c9FTD/ALS mutation. FTD suspected in 2/15 ALS patients was not confirmed owing to motor impairment. Nine probands reported first/second degree relatives with ALS or FTD/ALS; 5 probands reported relatives with FTD/dementia only and 2 probands reported no family history of ALS or FTD/dementia. One proband was adopted. All patients had El Escorial possible/probable/definite ALS except for a male with suspected ALS. Onset was bulbar in 2 patients (1 ALS; 1 FTD/ALS) and spinal in 16. Median onset age was 56 years (41-72yr). Median survival was 2.3 years (1-6.3yr) in 11 deceased; brain/spinal cord in 5 demonstrated TDP-43 pathology typical of ALS, with extramotor brain pathology in 2 FTD/ALS. Conclusions: The c9FTD/ALS phenotype of our patients was predominantly classical ALS with spinal onset. Frontotemporal cognitive impairment antedated motor signs in 2/3 FTD/ALS. Survival ranged from 1 to >6 years. c9FTD/ALS in 2 sporadic ALS patients may represent incomplete penetrance, incomplete ascertainment or new mutations and requires further study. Occurrence of FTD alone in family members supports consideration of FTD in first or second degree relatives of ALS patients as a potential marker of c9FTD/ALS. Supported by: ALS Association, Mayo Foundation and MCF ALS Center donor funds, NIH R01 NS065782 and R01 AG026251, NIH/NINDS 1RC2NS070276, NS057567, P50NS072187-01S2, Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Disclosure: Dr. Boylan has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rush has nothing to disclose. Dr. Desaro has nothing to disclose. Dr. Johnston has nothing to disclose. Dr. Kryston has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Dickson has nothing to disclose. Dr. Rademakers has nothing to disclose.
C9ORF72
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Frontotemporal lobar degeneration
Executive dysfunction
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Frontotemporal lobar degenerations are clinically, genetically, and molecularly heterogeneous diseases characterized by mainly frontal and temporal atrophy and affecting behavioral, language, cognitive, and motor functions. The term frontotemporal dementia incorporates 3 distinct clinical syndromes seen in frontotemporal degenerations: behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease syndrome are also associated with frontotemporal lobar degenerations. The neuropathologic hallmark of frontotemporal lobar degenerations is accumulation of abnormal proteins in the cytoplasm and nuclei of neurons and glial cells. Proteins involved in pathologic processes that represent the basis for frontotemporal lobar degeneration classification are tau protein, transactive response DNA-binding protein of 43 kDa, and "fused in sarcoma" protein. The aim of this review is to provide a summary of practical approaches for neuropathologic diagnostics of the rapidly evolving classifications of frontotemporal lobar degenerations.
Frontotemporal lobar degeneration
Semantic dementia
Corticobasal degeneration
Primary progressive aphasia
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Frontotemporal lobar degeneration
Semantic dementia
Primary progressive aphasia
Degeneration (medical)
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C9ORF72
TARDBP
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Frontotemporal dementia is the second most common early onset dementia after Alzheimer disease. Frontotemporal dementias are a complex group of dementias. The clinical diagnosis can be perplexing because of concurring psychiatric and neurologic syndromes. Frontotemporal lobar degeneration, the underlying pathology, represents an emerging group of proteinopathies. Genetic factors play an important part in the etiologies of dementias. This article overviews current defining characteristics of frontotemporal dementias known also as frontotemporal lobar degenerations.
Frontotemporal lobar degeneration
Semantic dementia
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Frontotemporal lobar degeneration
Pathogenesis
Exome
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