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Project

Understanding lysosomal dysfunction in the frontotemporal dementiaamyotrophic lateral sclerosis spectrum of neurodegenerative disorders.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis
(ALS) are two related incurable neurodegenerative disorders typically
striking people in mid-life. Loss of neurons in the frontal and temporal
lobes in FTD gives rise to behavioural changes and language
disturbances. Loss of neurons of the motor system in ALS causes
progressive muscle weakness and wasting. Due to the progressive
nature of FTD and ALS it has devastating effect on patients and their
families. Although the disease presentation of FTD and ALS is very
different, there is substantial overlap in the disease mechanisms
leading to neuronal loss. A key feature in about 50% of FTD and in
more than 95% of ALS is the aggregation in of a protein called TDP-
43. How aggregation of this protein is brougth about and how it
causes neuronal death is not known. Such TDP-43 aggregation is
also present in two hereditary forms of FTD and ALS, caused by
mutations in the progranulin gene and in the C9orf72 gene, allowing
us to study the mechanisms leading to TDP-43 aggregation in stem
cell models derived from patients suffering from the disease. We
recently observed that the lysosomes look abnormal and
dysfunctional in neurons made from such patient-derived stem cells.
Lysosomes play an important role in the removal of insoluble proteins
such as TDP-43. Therefore, a better understanding of how the
lysosomal problems can contribute to the aggregation of TDP-43 will
be crucial to devolop treatments for these disorders.

Date:1 Jan 2022 →  Today
Keywords:Frontotemporal dementia, Lysosomal dysfunction, Progranulin and C9orf72
Disciplines:Neurological and neuromuscular diseases, Cell physiology, Medical proteomics