Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology

Yang, Hyun Sik; White, Charles C.; Klein, Hans Ulrich; Yu, Lei; Gaiteri, Chris; Ma, Yiyi; Felsky, Daniel; Mostafavi, Sara; Petyuk, Vladislav; Sperling, Reisa A.; Ertekin-Taner, Nilüfer; Schneider, Julie A.; Bennett, David A.; Jager, Philip L. De

doi:10.1016/j.neuron.2020.05.010

Cited by 35 publications

(39 citation statements)

References 74 publications

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“…Subsequently, genetic linkages were identified with a much broader spectrum of other neurodegenerative disorders including limbic-predominant age-related TDP-43 encephalopathy, Parkinson's disease and late-onset Alzheimer's disease (22,23,38). Moreover, genetic links were also confirmed with dissociation of cognitive performance in elderlies and differential aging in humans (16,30,45,47) as well as with increased neuronal proportion in Alzheimer's disease (16). Recently, a mutation in TMEM106B was identified as the underlying cause for a hypomyelinating leukodystrophy (35,46,51).…”

Section: Discussionmentioning

confidence: 98%

“…Variations in TMEM106B were shown to affect the course of disease in both GRN-and C9orf72 carriers (7,8,28,40,42 (3,12,13,(22)(23)(24)31,38,48). Furthermore, TMEM106B was shown to play a role in the dissociation of cognition and neuropathology in elderly people (45) and TMEM106B was identified as a key genetic determinant of differential aging in the cerebral cortex (30,47). Finally, a dominant mutation in TMEM106B leads to a familial hypomyelinating leukodystrophy (35,46).…”

Section: Introductionmentioning

confidence: 99%

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Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non‐motor dysfunction

D’Hooge

Damme

2020

Brain Pathology

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Genetic variants in TMEM106B are a major risk factor for several neurodegenerative diseases including frontotemporal degeneration, limbic-predominant age-related TDP-43 encephalopathy, Parkinson's disease, late-onset-Alzheimer's disease and constitute a genetic determinant of differential aging. TMEM106B encodes an integral lysosomal membrane protein but its precise physiological function in the central nervous system remains enigmatic. Presently, we aimed to increase understanding of TMEM106B contribution to general brain function and aging. We analyzed an aged cohort of Tmem106b knockout-, heterozygote and wild-type mice in a behavioral test battery including assessments of motor function as well as, social, emotional and cognitive function. Aged Tmem106b knockout (KO) mice displayed diverse behavioral deficits including motor impairment, gait defects and reduced startle reactivity. In contrast, no prominent deficits were observed in social, emotional or cognitive behaviors. Histologically, we observed late-onset loss of Purkinje cells followed by reactive gliosis in the cerebellum, which likely contributed to progressive decline in motor function and gait defects in particular. Reactive gliosis was not restricted to the cerebellum but observed in different areas of the brain including the brain stem and parts of the cerebral cortex. Surviving Purkinje cells showed vacuolated lysosomes in the axon initial segment, implicating TMEM106B-dependent lysosomal trafficking defects as the underlying cause of axonal and more general neuronal dysfunction contributing to behavioral impairments. Our experiments help to elucidate how TMEM106B affects spatial neuronal homeostasis and exemplifies a critical role of TMEM106B in neuronal cells for survival.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non‐motor dysfunction

D’Hooge

Damme

2020

Brain Pathology

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“…Secondly, a recent study identified GRN and TMEM106B as two of the five risk factors for a recently recognized disease entity, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (Nelson et al , ). These two genes were also found to be associated with TDP‐43 proteinopathy and coordinate with each other to regulate gene expression in a genome‐wide transcription study (Yang et al , ). Furthermore, GRN and/or TMEM106B polymorphisms are associated with FTLD caused by C9ORF72 mutations (van Blitterswijk et al , ; Deming & Cruchaga, ; Gallagher et al , ; Lattante et al , ), cognitive impairment in amyotrophic lateral sclerosis (ALS) (Vass et al , ) and Parkinson's disease (PD) (Baizabal‐Carvallo & Jankovic, ; Tropea et al , ), and pathological presentation of Alzheimer's disease (AD) (Lee et al , ; Rutherford et al , ; Kamalainen et al , ; Perry et al , ; Sheng et al , ; Xu et al , ).…”

Section: Introductionmentioning

confidence: 99%

Loss of TMEM 106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice

et al. 2020

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Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B, a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD-related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis.

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“…In another example, the effects of two genetic variants, APOEε4 and a haplotype in TMEM106B, were shown to converge on altered expression of a group of co-expressed genes called module 110: they independently alter the expression of module 110, which then contributes to the accumulation of TDP-43 proteinopathy. This model was developed in a data-driven manner using rigorous statistics, and, while the model needs to be validated, it is consistent with known biology of TDP-43 pathology, suggesting that large datasets can begin to define complex relationships (43).…”

Section: Transcriptome In Admentioning

confidence: 99%

Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms

Klein

Jager

2020

Brain Pathology

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The past decade has seen the maturation of multiple different forms of high‐dimensional molecular profiling to the point that these methods could be deployed in initially hundreds and more recently thousands of human samples. In the field of Alzheimer's disease (AD), these profiles have been applied to the target organ: the aging brain. In a growing number of cases, the same samples were profiled with multiple different approaches, yielding genetic, transcriptomic, epigenomic and proteomic data. Here, we review lessons learned so far as we move beyond quantitative trait locus (QTL) analyses which map the effect of genetic variation on molecular features to integrate multiple levels of “omic” data in an effort to identify the molecular drivers of AD. One thing is clear: no single layer of molecular or “omic” data is sufficient to capture the variance of AD or aging‐related cognitive decline. Nonetheless, reproducible findings are emerging from current efforts, and there is evidence of convergence using different approaches. Thus, we are on the cusp of an acceleration of truly integrative studies as the availability of large numbers of well‐characterized brain samples profiled in three or more dimensions enables the testing, comparison and refinement of analytic methods with which to dissect the molecular architecture of the aging brain.

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Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology

Cited by 35 publications

References 74 publications

Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non‐motor dysfunction

Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non‐motor dysfunction

Loss of TMEM 106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice

Considerations for integrative multi‐omic approaches to explore Alzheimer's disease mechanisms

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