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The hypothalamus as a key mediator of neurodegenerative disorders

Bergh, Sofia LU (2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Background: There are currently no major disease-modifying treatments for neurodegenerative disorders such as Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). HD is caused by a CAG repeat expansion in the huntingtin gene and is characterised by the accumulation of mutant huntingtin (mHTT) protein. ALS is defined by the degeneration of motor neurons connecting the brain, spinal cord and muscles, while FTD involves damage to cortical regions, primarily the frontal and temporal lobes. ALS often co-occur with FTD, with the common denominator linking these disorders being the transactive response DNA binding protein of 43 kDa (TDP-43). What connects HD, ALS-FTD and other distinct... (More)
Background: There are currently no major disease-modifying treatments for neurodegenerative disorders such as Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). HD is caused by a CAG repeat expansion in the huntingtin gene and is characterised by the accumulation of mutant huntingtin (mHTT) protein. ALS is defined by the degeneration of motor neurons connecting the brain, spinal cord and muscles, while FTD involves damage to cortical regions, primarily the frontal and temporal lobes. ALS often co-occur with FTD, with the common denominator linking these disorders being the transactive response DNA binding protein of 43 kDa (TDP-43). What connects HD, ALS-FTD and other distinct neurodegenerative disorders is pathology of the hypothalamus—a key regulator of emotion and metabolism. Clinical features such as anxiety, depression and body weight dysregulation are common across these disorders and may be linked to hypothalamic dysfunction. We hypothesize that the hypothalamus is vulnerable to mHTT and TDP-43 toxicity, and that damage in this region contributes to the observed metabolic and psychiatric phenotypes in people affected by HD or ALS-FTD. We therefore aimed to identify the structure-to-function relationship between the hypothalamus and its circuitry and the development of the psychiatric and metabolic features of HD and ALS-FTD.Results: We demonstrated that TDP-43 overexpression in the hypothalamus of mice was sufficient to induce ALS-FTD-like pathology, including the formation of cytoplasmic TDP-43 localisation with inclusions and the development of metabolic and emotional deficits (Paper I). In addition, we established the RNA/DNA autophagy protein SID1 transmembrane family member 2 (SIDT2) as a novel pathological hallmark in HD (Paper II). SIDT2 protein levels are significantly reduced in advanced HD and SIDT2-immunoreactive inclusions are present in postmortem human brain tissue from HD cases. Given that SIDT2 overexpression in vivo and in vitro reduces HTT load independent of canonical degradation pathways, the SIDT2 system represents a promising therapeutic avenue. Lastly, we showed that neurons expressing oxytocin—a neuropeptide implicated in social behaviour, anxiety and depression—are susceptible to both mHTT and TDP-43 toxicity (Paper III and IV). Interestingly, pathology in oxytocin neurons was insufficient to generate behavioural and metabolic dysfunction, suggesting that other neuronal populations may play a more prominent role in the pathogenesis of HD and ALS-FTD.Conclusion: This thesis demonstrates the involvement of the hypothalamus in neurodegenerative disorders characterised by TDP-43 and mHTT pathology. Our results indicate that hypothalamic pathology may be a convergence point of these disease processes and therefore represents a potential therapeutic target. Furthermore, the observed deficits in the SIDT2 pathway in HD suggest that SIDT2 is a promising therapeutic candidate. (Less)
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author
supervisor
opponent
  • Professor Bates, Gillian, University College London
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2026:60
pages
99 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63278239686
defense date
2026-05-06 13:00:00
ISSN
1652-8220
ISBN
978-91-8021-858-0
language
English
LU publication?
yes
id
c091032b-b6d9-44c4-9b57-b3e65d3f0281
date added to LUP
2026-04-08 15:58:40
date last changed
2026-04-21 07:25:25
@phdthesis{c091032b-b6d9-44c4-9b57-b3e65d3f0281,
  abstract     = {{Background: There are currently no major disease-modifying treatments for neurodegenerative disorders such as Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). HD is caused by a CAG repeat expansion in the huntingtin gene and is characterised by the accumulation of mutant huntingtin (mHTT) protein. ALS is defined by the degeneration of motor neurons connecting the brain, spinal cord and muscles, while FTD involves damage to cortical regions, primarily the frontal and temporal lobes. ALS often co-occur with FTD, with the common denominator linking these disorders being the transactive response DNA binding protein of 43 kDa (TDP-43). What connects HD, ALS-FTD and other distinct neurodegenerative disorders is pathology of the hypothalamus—a key regulator of emotion and metabolism. Clinical features such as anxiety, depression and body weight dysregulation are common across these disorders and may be linked to hypothalamic dysfunction. We hypothesize that the hypothalamus is vulnerable to mHTT and TDP-43 toxicity, and that damage in this region contributes to the observed metabolic and psychiatric phenotypes in people affected by HD or ALS-FTD. We therefore aimed to identify the structure-to-function relationship between the hypothalamus and its circuitry and the development of the psychiatric and metabolic features of HD and ALS-FTD.Results: We demonstrated that TDP-43 overexpression in the hypothalamus of mice was sufficient to induce ALS-FTD-like pathology, including the formation of cytoplasmic TDP-43 localisation with inclusions and the development of metabolic and emotional deficits (Paper I).  In addition, we established the RNA/DNA autophagy protein SID1 transmembrane family member 2 (SIDT2) as a novel pathological hallmark in HD (Paper II). SIDT2 protein levels are significantly reduced in advanced HD and SIDT2-immunoreactive inclusions are present in postmortem human brain tissue from HD cases. Given that SIDT2 overexpression in vivo and in vitro reduces HTT load independent of canonical degradation pathways, the SIDT2 system represents a promising therapeutic avenue. Lastly, we showed that neurons expressing oxytocin—a neuropeptide implicated in social behaviour, anxiety and depression—are susceptible to both mHTT and TDP-43 toxicity (Paper III and IV). Interestingly, pathology in oxytocin neurons was insufficient to generate behavioural and metabolic dysfunction, suggesting that other neuronal populations may play a more prominent role in the pathogenesis of HD and ALS-FTD.Conclusion: This thesis demonstrates the involvement of the hypothalamus in neurodegenerative disorders characterised by TDP-43 and mHTT pathology. Our results indicate that hypothalamic pathology may be a convergence point of these disease processes and therefore represents a potential therapeutic target. Furthermore, the observed deficits in the SIDT2 pathway in HD suggest that SIDT2 is a promising therapeutic candidate.}},
  author       = {{Bergh, Sofia}},
  isbn         = {{978-91-8021-858-0}},
  issn         = {{1652-8220}},
  language     = {{eng}},
  number       = {{2026:60}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{The hypothalamus as a key mediator of neurodegenerative disorders}},
  url          = {{https://lup.lub.lu.se/search/files/246880036/Avhandling_Sofia_Bergh.pdf}},
  year         = {{2026}},
}