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Since cerebellar Purkinje cells are known to play an important role in controlling balance, we next investigated motor function in aged I Tmem106b-/-, Tmem106b+/-, i and WT mice (15 months of age) using a dowel test. We next examined Purkinje cell numbers in younger mice; however, no significant difference in terms of Purkinje cell number was observed between I Tmem106b-/- i and WT mice at 3 and 8 months of age (Figure 1B, C). Taken together, these results are in line with Purkinje cell loss in I Tmem106b-/- i cerebellum and further implicate inflammation in Tmem106b deficiency-induced Purkinje cell loss. [Extracted from the article]

Progranulin (PGRN) and transmembrane protein 106B (TMEM106B) are important lysosomal proteins implicated in frontotemporal lobar degeneration (FTLD) and other neurodegenerative disorders. Loss‐of‐function mutations in progranulin (GRN) are a common cause of FTLD, while TMEM106B variants have been shown to act as disease modifiers in FTLD. Overexpression of TMEM106B leads to lysosomal dysfunction, while loss of Tmem106b ameliorates lysosomal and FTLD‐related pathologies in young Grn−/− mice, suggesting that lowering TMEM106B might be an attractive strategy for therapeutic treatment of FTLD‐GRN. Here, we generate and characterize older Tmem106b−/−Grn−/− double knockout mice, which unexpectedly show severe motor deficits and spinal cord motor neuron and myelin loss, leading to paralysis and premature death at 11–12 months. Compared to Grn−/−, Tmem106b−/−Grn−/− mice have exacerbated FTLD‐related pathologies, including microgliosis, astrogliosis, ubiquitin, and phospho‐Tdp43 inclusions, as well as worsening of lysosomal and autophagic deficits. Our findings confirm a functional interaction between Tmem106b and Pgrn and underscore the need to rethink whether modulating TMEM106B levels is a viable therapeutic strategy. Synopsis: Loss of TMEM106B has been suggested as therapeutic treatment of FTLD‐GRN. This study shows that loss of Tmem106b exacerbates FTLD pathologies and causes spinal cord motor neuron loss and myelin degeneration leading to motor deficits in Grn deficient mice. Loss of Tmem106b leads to severe motor deficits and premature death in Grn deficient mice.Loss of Tmem106b leads to spinal cord motor neuron loss and myelin degeneration in Grn deficient mice.Loss of Tmem106b exacerbates FTLD‐related pathologies, including microgliosis, astrogliosis, and ubiquitin and phospho‐Tdp43 inclusions in Grn deficient mice.Loss of Tmem106b exacerbates lysosomal and autophagic deficits in Grn deficient mice. [ABSTRACT FROM AUTHOR]

Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b-/- mouse model. We included 10 Tmem106b+/+ (wild-type), 10 Tmem106b+/- and 10 Tmem106-/- mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b-/- and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b-/- mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b-/- mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN -associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN -associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology. [Display omitted] • Progranulin loss induces microgliosis in white matter of Grn knockout (KO) mice • Microglial lysosomes accumulate myelin debris in Grn KO mice and GRN -related FTD • Lysosomal degradation of myelin debris is impaired in Grn KO cultured microglia • Reducing Ctsd exacerbates myelin debris and pTDP-43 accumulation in Grn KO mice Wu et al. show increased microgliosis in white matter of Grn knockout mice. Microglial lysosomes accumulate myelin debris in both Grn knockout mice and patients with GRN -associated FTD, and reducing cathespin D levels exacerbates both myelin debris accumulation and pTdp-43 aggregation. Thus, lysosomal dysfunction affects these pathologies in GRN -related FTD. [ABSTRACT FROM AUTHOR]

The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer's disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD. [ABSTRACT FROM AUTHOR]