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NIH grant 1K99AG103868-01: Metabolic Regulation of RNA Processing in Alzheimer's Disease and Related Neurodegeneration
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Larissa Traxler. Award: $124124.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY
Alzheimer’s disease (AD) and Amyotrophic lateral sclerosis (ALS) cause progressive loss of cortical and motor
neurons, respectively, yet they share overlapping mechanisms, including RNA-binding protein (RBP)
mislocalization and splicing dysfunction. Mechanisms driving selective neuronal vulnerability remain poorly
understood, in part because most model systems fail to capture the adult neuronal RNA isoform landscape.
Directly converted induced neurons (iNs) from patient fibroblasts overcome this limitation by retaining donor age,
genetic background, and mature neuronal metabolism, while expressing adult human-specific isoforms absent
in iPSC-derived or animal models. Importantly, iNs naturally exhibit disease-relevant phenotypes such as TDP-
43 mislocalization, tau pathology, and splicing alterations, that faithfully reflect in-vivo human disease signatures.
My preliminary data established a link between dysregulated acetyl-CoA metabolism and alternative splicing in
AD. I identified ATP-citrate lyase (ACLY) as a major nuclear acetyl-CoA-producing enzyme in AD iNs and
demonstrated that its inhibition reverses disease-associated splicing of APP and PKM. However, the causal
relationship between acetyl-CoA metabolism, RBP hyper-acetylation and mislocalization, and
neurodegeneration across diseases remains unknown. I hypothesize that dysregulated acetyl-CoA metabolism
drives RBP hyper-acetylation, mislocalization, and isoform dysregulation, resulting in selective neuronal
degeneration in AD and ALS. In the K99 phase, I will determine which acetyl-CoA-producing pathways drive
RBP acetylation and splicing regulation in AD iNs and extend this framework to ALS by investigating how
cytosolic acetyl-CoA modulates TDP-43 acetylation and aggregation in patient-derived induced motor neurons
(iMNs). This phase will provide advanced training in ALS biology and multi-dimensional proteo-genomics
(AVITI24), broadening my skills beyond AD and metabolism. During the R00 phase, I will integrate metabolic
isotope tracing with technologies acquired during the K99 phase to perform CRISPRi screening on the AVITI24
platform and long-read RNA sequencing integrated with splice reporters to identify shared and disease-specific
metabolic pathways driving vulnerability of cortical and motor neurons in AD and ALS. This project bridges my
current strengths in metabolism and disease modeling with new expertise in ALS and single-cell multi-omics,
establishing a mechanistic foundation for my independent research program on metabolic regulation of RBP
function and selective neurodegeneration. To achieve these objectives, I will receive support from a diverse team
of mentors and advisors with expertise in disease modeling using directly converted neurons, RNA biology,
bioinformatic splice analysis, and clinical aspects of AD and ALS. I will further engage in career development
training, including ethics, leadership, and grant writing, to facilitate my transition to independence.document fetched 2026-09-20 02:42