In the healthy brain, the DNA binding protein TDP-43 control gene expression. But in neurodegenerative diseases like FTD, HD and ALS, toxic inclusions of TDP-43 are usually found outside of the brain cells’ nuclei. Although clinically distinct, these disorders often share unexpected symptoms, including psychiatric disturbances and metabolic dysregulation. Hypothalamus may be the key to understanding why.
"These neurodegenerative disorders all have disease-related changes in a brain region called the hypothalamus. This brain region plays a crucial role in controlling emotions and metabolism, which is affected in these diseases”, explains Professor Åsa Petersén.
Åsa Petersén, together with Sofia Bergh, set out to explore whether TDP-43 harms the hypothalamus.
“We aimed to find out if increasing the amount of TDP-43 in the hypothalamus directly leads to changes in the hypothalamus, metabolic problems and emotional changes”, adds Sofia Bergh, first author of the paper.
The role of TDP-43 in neurodegeneration remains incomplete. One unanswered question is how TDP-43 can become harmful even without a genetic mutation. The current study shows that elevating the levels of TDP-43 in the hypothalamus of healthy mice was enough to recapitulate features of neurodegenerative disease. Too much TDP-43 in the hypothalamus caused problems similar to those seen in persons with ALS and frontotemporal dementia. This includes loss of specific cells with neuropeptides that control metabolism and emotions, and seems to result in apathy.
Even normal TDP-43 started behaving like the harmful versions seen in patients, moving to the wrong locations in cells and forming clumps which we think result in disease development”, explains Åsa Petersén.
Psychiatric and metabolic symptoms in neurodegenerative diseases have long been overlooked, despite their profound impact on patients' quality of life. This study offers crucial insights into the origins of these non-motor symptoms. In addition to deepening our understanding of disease mechanisms it opens new avenues for treating these complex conditions.
