Prion-like mechanisms in neurodegenerative disease: Implications for Huntington's disease therapy

Area of Science:

• Neuroscience
• Genetics
• Regenerative Medicine

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene, leading to toxic misfolded huntingtin protein (mHTT).
• Current HD treatments are palliative, necessitating research into novel therapeutic strategies like gene and stem cell therapies.
• Stem cell transplants aim to replace or support neurons, but a "prion-like" transfer of mHTT aggregates to grafts has been observed.

Purpose of the Study:

• To review stem cell transplantation efficacy in Huntington's disease patients.
• To focus on the "prion-like" transfer of misfolded huntingtin protein (mHTT) aggregates from host neurons to transplanted cells.
• To evaluate autotransplantation of reprogrammed stem cells as a potential therapeutic option for HD.

Main Methods:

• Review of existing literature on stem cell transplantation in Huntington's disease patients.
• Analysis of studies reporting on the "prion-like" transfer of misfolded huntingtin protein (mHTT) aggregates.
• Examination of therapeutic efficacy data for various stem cell types, including mesenchymal stem cells, neural stem cells, and reprogrammed stem cells.

Main Results:

• Stem cell transplants, including xenografts and allografts, have been used in HD patients with varying efficacy.
• A "prion-like" mechanism facilitates the transfer of misfolded huntingtin protein (mHTT) aggregates from host neurons to grafted cells and surrounding tissues.
• This transfer phenomenon is observed even in autotransplantation paradigms.

Conclusions:

• Autotransplantation of reprogrammed stem cells presents a promising therapeutic avenue for Huntington's disease (HD).
• Further research is crucial to fully understand the transfer of misfolded huntingtin protein (mHTT) aggregates after transplantation of gene-corrected cells.
• Addressing mHTT aggregate transfer is essential for optimizing the long-term success of stem cell-based therapies for HD.