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TMEM106B deficiency impairs cerebellar myelination and synaptic integrity with Purkinje cell loss
Tuancheng Feng1, Lin Luan1, Isabel Iscol Katz1
1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA.
Abstract:
TMEM106B, a type II lysosomal transmembrane protein, has recently been associated with brain aging, hypomyelinating leukodystrophy, frontotemporal lobar degeneration (FTLD) and several other brain disorders. TMEM106B is critical for proper lysosomal function and TMEM106B deficiency leads to myelination defects, FTLD related pathology, and motor coordination deficits in mice. However, the physiological and pathological functions of TMEM106B in the brain are still not well understood. In this study, we investigate the role of TMEM106B in the cerebellum, dysfunction of which has been associated with FTLD and other brain disorders. We found that TMEM106B is ubiquitously expressed in neurons in the cerebellum, with the highest levels in the Purkinje neurons. Aged TMEM106B-deficient mice show significant loss of Purkinje neurons specifically in the anterior lobe of the cerebellum. Increased microglia and astrocyte activation, as well as an accumulation of ubiquitinated proteins, p62 and TDP-43 were also detected in the cerebellum of aged TMEM106B deficient mice. In the young mice, myelination defects and a significant loss of synapses between Purkinje and deep cerebellar nuclei neurons were observed. Interestingly, TMEM106B deficiency causes distinct lysosomal phenotypes in different types of neurons and glia in the cerebellum and frontal cortex. In humans, TMEM106B rs1990622 risk allele (T/T) is associated with increased Purkinje neuron loss. Taken together, our studies support that TMEM106B regulates lysosomal function in a cell-type-specific manner and TMEM106B is critical for maintaining synaptic integrity and neural functions in the cerebellum.
Insights
Transmembrane protein 106B (TMEM106B) is crucial for cerebellar neuron health and lysosomal function. TMEM106B deficiency causes neuron loss, myelination defects, and synaptic issues, impacting brain aging and neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Transmembrane protein 106B (TMEM106B) is linked to brain aging and neurodegenerative disorders like frontotemporal lobar degeneration (FTLD).
- TMEM106B is essential for lysosomal function, and its deficiency causes myelination defects and motor deficits.
- The precise roles of TMEM106B in the brain, particularly the cerebellum, remain incompletely understood.
Purpose of the Study:
- To investigate the role of TMEM106B in cerebellar physiology and pathology.
- To determine the cell-type-specific functions of TMEM106B in the cerebellum and frontal cortex.
- To explore the association between TMEM106B variants and Purkinje neuron loss in humans.
Main Methods:
- Analysis of TMEM106B expression in cerebellar neurons, including Purkinje cells.
- Phenotypic characterization of TMEM106B-deficient mice at different ages, assessing neuronal loss, glial activation, protein aggregation, and myelination.
- Investigation of lysosomal phenotypes in various cell types within the cerebellum and frontal cortex.
- Correlation analysis of TMEM106B genetic variants (rs1990622) with Purkinje neuron loss in human populations.
Main Results:
- TMEM106B is widely expressed in cerebellar neurons, notably in Purkinje neurons.
- Aged TMEM106B-deficient mice exhibit significant Purkinje neuron loss, increased glial activation, and accumulation of ubiquitinated proteins (p62, TDP-43) in the cerebellum.
- Young TMEM106B-deficient mice display myelination defects and synaptic loss in the cerebellum.
- TMEM106B deficiency induces distinct lysosomal alterations in different neuronal and glial cell types.
- The TMEM106B rs1990622 risk allele (T/T) is associated with increased Purkinje neuron loss in humans.
Conclusions:
- TMEM106B regulates lysosomal function in a cell-type-specific manner within the cerebellum and frontal cortex.
- TMEM106B is critical for maintaining synaptic integrity and neuronal function in the cerebellum.
- Dysfunction of TMEM106B contributes to cerebellar pathology relevant to brain aging and neurodegenerative diseases.
