A shared feature of neurodegenerative disorders is accumulation of aggregated proteins within neurons: Tau in Alzheimer's disease; alpha-synuclein in Parkinson's disease; huntingtin in Huntington's disease; and TDP43 in amyotrophic lateral sclerosis. In this episode Ai Yamamoto – an Associate Professor Neurology at Columbia University – talks about the trail of discoveries that led to the identification of a protein called ALFY that can prevent and reverse the accumulation of such pathogenic proteins. Remarkably, her team and collaborators found that some people have a variant of the gene encoding ALFY that confers resistance of those individuals to Huntington's disease. This discovery opens many new and exciting directions for future research aimed at better understanding what goes wrong in neurodegenerative disorders and for developing interventions counteract the disease process.

LINKS

Yamamoto Laboratory web page: https://www.aiyamamoto-lab.org/

Dr. Yamamoto's publications: https://scholar.google.com/citations?hl=en&user=HuJslgMAAAAJ&pagesize=80&view_op=list_works

Key research articles:

https://www.cell.com/action/showPdf?pii=S0896-6273%2825%2900624-5

file:///Users/markmattson/Downloads/s41583-022-00588-3.pdf

https://www.cell.com/action/showPdf?pii=S0896-6273%2819%2931045-1

Remarkable advances are being made in the development and clinical applications of stimulation devices that enable recovery of motor function in patients who have suffered a spinal cord injury, a stroke, and even those with rare disabling genetic disorders. At the forefront of this research is Marco Capogrosso at the University of Pittsburgh. He has shown that certain patterns of stimulation of sensory pathways in the spinal cord can activate motor neurons that were otherwise silenced by the injury or stroke. Initial clinical trials have shown that this approach results in recovery of function which are in some cases very dramatic in patients that have had a stroke, a spinal cord injury, and in people with the genetic disorder spinal muscular atrophy. In this episode Dr. Capogrosso talks about the development of this stimulation-based therapeutic approach, the clinical trials, and the potential applications of this technology to other neurodegenerative disorders.

LINKS

Dr. Capogrosso's profile at the University of Pittsburgh:

https://www.neurosurgery.pitt.edu/people/marco-capogrosso

Key studies discussed in this podcast:

Stroke

https://pmc.ncbi.nlm.nih.gov/articles/PMC10291889/pdf/nihms-1904547.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC12393459/pdf/nihpp-rs7271578v1.pdf

Spinal cord injury

https://pmc.ncbi.nlm.nih.gov/articles/PMC5108412/pdf/emss-70056.pdf

https://www.cell.com/neuron/fulltext/S0896-6273(25)00658-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627325006580%3Fshowall%3Dtrue#

Spinal muscular atrophy

https://www.nature.com/articles/s41591-024-03484-8

Dietary iron is essential for health as it plays important roles in the ability of hemoglobin to carry oxygen throughout the body and brain. In addition, iron is involved in various functions in cells including the generation of ATP in mitochondria and DNA synthesis. The vast majority of iron is bound to proteins such as ferritin and heme. However, in its ionic form (Fe2+) iron can react with the hydrogen peroxide produced from mitochondrial superoxide radical to generate the highly toxic hydroxyl radical. Hydroxyl radical damages DNA and can also act on the carbon=carbon double bonds in unsaturated member lipids and trigger an autocatalytic process called lipid peroxidation. Lipid peroxidation in neurons occurs in Alzheimer's and Parkinson's disease and may play a major role in the death of neurons in these disorders a process called 'ferroptosis'. In this episode I talk with Scott Ayton a Professor at the Florey Institute at the University of Melbourne about both the normal functions of iron in neurons, its involvement in Alzheimer's and Parkinson's disease, and the potential of interventions that prevent ferroptosis in the treatment of these disorders.

LINKS

Professor Aytons profile at the Florey Institute:

https://florey.edu.au/researcher/scott-ayton/

Relevant articles

file:///Users/markmattson/Downloads/s41583-025-00930-5%20(1).pdf

https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1196/annals.1306.004?saml_referrer

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2209254

https://jamanetwork.com/journals/jamaneurology/article-abstract/2825846