What we know about TMEM106B in neurodegeneration

Alexandra M. Nicholson, Rosa V Rademakers

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7. In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) mutations, as well as Alzheimer’s disease and hippocampal sclerosis. We further summarize what is currently known about the previously uncharacterized TMEM106B protein and its role as a potential regulator of lysosomal function, and we discuss how modifying TMEM106B levels might uncover promising therapeutic strategies for individuals suffering from TDP-43 proteinopathy.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Aug 20 2016

Fingerprint

Frontotemporal Dementia
DNA-Binding Proteins
Frontotemporal Lobar Degeneration
Chromosomes, Human, Pair 9
Mutation
Chromosomes, Human, Pair 7
Genome-Wide Association Study
Sclerosis
Temporal Lobe
Neurodegenerative Diseases
Open Reading Frames
Dementia
Autopsy
Alzheimer Disease
Brain
Proteins
Therapeutics

Keywords

  • Frontotemporal dementia
  • Genetic association
  • Lysosomes
  • TDP-43
  • TMEM106B

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

What we know about TMEM106B in neurodegeneration. / Nicholson, Alexandra M.; Rademakers, Rosa V.

In: Acta Neuropathologica, 20.08.2016, p. 1-13.

Research output: Contribution to journalArticle

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