Dataset Information

Case analysis of early-onset Alzheimer's disease associated with TBK1 p.Tyr235Phe gene mutation.

ABSTRACT: TANK1-binding kinase 1 (TBK1) is mainly involved in the regulation of various cellular pathways through the autophagic lysosomal system, and the loss of function or hypofunction caused by TBK1 gene mutation mainly leads to frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and ALS-FTLD. Alzheimer's disease (AD) due to TBK1 gene mutation is extremely rare, and only one case has been reported in China so far. In this report, we described a patient with early-onset AD (EOAD) in whom a new probable pathogenic variant c.704A>T (p.Tyr235Phe) in the TBK1 gene was identified by a whole-genome sequencing analysis. It is suggested that FTLD gene mutation may exist in patients with clinical manifestations of AD.

SUBMITTER: Li P

PROVIDER: S-EPMC9671219 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case analysis of early-onset Alzheimer's disease associated with TBK1 p.Tyr235Phe gene mutation.

Li Pan P Y Yuanyuan Y Cai Hao H Zhang Huihong H Zhou Yuying Y

Frontiers in neurology 20221103

TANK1-binding kinase 1 (TBK1) is mainly involved in the regulation of various cellular pathways through the autophagic lysosomal system, and the loss of function or hypofunction caused by TBK1 gene mutation mainly leads to frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and ALS-FTLD. Alzheimer's disease (AD) due to TBK1 gene mutation is extremely rare, and only one case has been reported in China so far. In this report, we described a patient with early-onset AD (E ...[more]

PMID: 36408501

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Project description:Presenilin-2 (PSEN2) mutation Thr421Met was identified from a 57-years old patient with early onset Alzheimer's disease (EOAD) for the first time in Korea. Previously, this mutation was discovered in an EOAD patient in Japan without a change on amyloid production from the cellular study. Both Korean and Japanese patients developed the disease in their 50s. Memory loss was prominent in both cases, but no additional clinical information was available on the Japanese patient. Magnetic resonance imaging (MRI) images of the Korean patient revealed asymmetric atrophies in both temporo-parietal lobes. In addition, amyloid positron emission tomography (PET) also revealed amyloid deposits in the gray matter of the temporo-parietal lobes asymmetrically. PSEN2 Thr421 was conserved among a majority of vertebrates (such as zebras, elephants, and giant pandas); hence, Thr421 could play an important role in its functions and any mutations could cause detrimental ramifications in its interactions. Interestingly, PSEN2 Thr421 could have homology with PSEN1 Thr440, as PSEN1 T440del mutations were reported from patients with AD or dementia with Lewy bodies. Hence, the changed amino acid from threonine to methionine of PSEN2 Thr421 could cause significant structural alterations in causing local protein dynamics, leading to its pathogenicity in EOAD. Lastly, PSEN2 Thr421Met may interact with other mutations in neurodegenerative disease related genes, which were found in the proband patient, such as ATP binding cassette subfamily A member 7 (ABCA7), Notch Receptor 3 (NOTCH3), or Leucine-rich repeat kinase 2 (LRRK2). These interactions of pathway networks among PSEN2 and other disease risk factors could be responsible for the disease phenotype through other pathways. For example, PSEN2 and ABCA7 may impact amyloid processing and reduce amyloid clearance. Interaction between PSEN2 and NOTCH3 variants may be associated with abnormal NOTCH signaling and a lower degree of neuroprotection. Along with LRRK2 variants, PSEN2 Thr421Met may impact neurodegeneration through Wnt related pathways. In the future, cellular studies of more than one mutation by CRISPR-Cas9 method along with biomarker profiles could be helpful to understand the complicated pathways.

Dataset Information

Case analysis of early-onset Alzheimer's disease associated with TBK1 p.Tyr235Phe gene mutation.

Publications

Case analysis of early-onset Alzheimer's disease associated with TBK1 p.Tyr235Phe gene mutation.

Similar Datasets

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