What we know about TMEM106B in neurodegeneration

Nicholson, Alexandra M.; Rademakers, Rosa

doi:10.1007/s00401-016-1610-9

Cited by 91 publications

(130 citation statements)

References 92 publications

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“…Although there is no evidence yet, some genetic modifiers or environmental factors may have a role in the phenotypic variability of PS. It is well-established that both caffeine intake [35] and exercise [36] can modify the disease presentation in parkinsonism and for TDP-43 proteinopathy ATXN2 [37] and TMEM106B [38] are recognized as genetic modifiers of penetrance. To date, no pathological analyses have been conducted on atypical PS cases and as such this remains a clinical phenomenon.…”

Section: Atypical Phenotypes Of Perry Syndromementioning

confidence: 99%

DCTN1-related neurodegeneration: Perry syndrome and beyond

Konno

Ross

Teive

et al. 2017

Parkinsonism & Related Disorders

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Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150Glued. Dynactin is a motor protein involved in axonal transport; the p150Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970’s but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history.

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Section: Atypical Phenotypes Of Perry Syndromementioning

confidence: 99%

DCTN1-related neurodegeneration: Perry syndrome and beyond

Konno

Ross

Teive

et al. 2017

Parkinsonism & Related Disorders

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“…For instance, in fALS the same mutations of VCP and C9orf72 are present in individuals with ALS, FTD, and other neurological syndromes [1,2], and mutations in KIF5A have been variably associated with hereditary spastic paraplegia, CharcotMarie-Tooth disease, and infant myoclonic epilepsy, as well as ALS [3]. This phenomenon in genetics is termed pleiotropy, and it is remarkably common across neurodegenerative diseases.…”

Section: Genes In Amyotrophic Lateral Sclerosis and Other Neurodegenementioning

confidence: 99%

Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

et al. 2018

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Background: Amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s diseases are age-related neurodegenerative diseases. ALS is not a single entity but a syndrome with many different causes. In all 3 diseases, gene mutations account for only 10–15% of cases. Many environmental and lifestyle factors have been implicated as risk factors for ALS, though none have been proven to cause the disease. It is generally believed that ALS results from interactions between environmental risk factors and genetic predisposing factors. The advent of next-generation sequencing and recent advances in research into environmental risk factors offer the opportunity to investigate these interactions. Summary: We propose a hypothesis to explain the syndrome of ALS based on the interaction of many individual environmental risk factors with many individual genetic predisposing factors. We hypothesize that there are many such combinations of individual, specific, genetic, and environmental factors, and that each combination can lead to the development of the syndrome of ALS. We also propose a hypothesis that explains the overlap between the age-related neurodegenerations and their genetic underpinnings. Age and duration of exposure are crucial factors in these age-related neurodegenerative diseases, and we consider how these may relate to gene-environment interactions. Key Messages: To date, genetic studies and environmental studies have investigated the causes of ALS separately. We argue that this univariate approach will not lead to discoveries of important gene-environment interactions. We propose new research approaches to investigating gene-environment interactions based on these hypotheses.

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“…TMEM106B was initially described as a risk modifier of FTLD-TDP by a genome-wide association study (GWAS) (Nicholson and Rademakers, 2016). FTLD-TDP risk association is increased in GRN mutation carriers where single-nucleotide polymorphisms (SNPs) in TMEM106B reduce disease penetrance (Finch et al, 2011; Van Deerlin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice

Klein

Takahashi

et al. 2017

Neuron

144

169

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SUMMARY Progranulin (GRN) and TMEM106B are associated with several common neurodegenerative disorders including frontotemporal lobar degeneration (FTLD). A TMEM106B variant modifies GRN-associated FTLD risk. However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn−/− and Tmem106b−/− mice, we show that while multiple lysosomal enzymes are increased in Grn−/− brain at both transcriptional and protein levels, TMEM106B deficiency causes reduction in several lysosomal enzymes. Remarkably, Tmem106b deletion from Grn−/− mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration, without improving lipofuscin, C1q or microglial accumulation. Mechanistically, TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal protein levels in Grn−/− neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal enzyme levels, and their interaction determines the extent of neurodegeneration.

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What we know about TMEM106B in neurodegeneration

Cited by 91 publications

References 92 publications

DCTN1-related neurodegeneration: Perry syndrome and beyond

DCTN1-related neurodegeneration: Perry syndrome and beyond

Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice

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