Laura P.w Ranum

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Alzheimer's and Dementia
• Developmental Cognitive Neuroscience
• Autism Spectrum Disorder
• Traumatic Brain Injury

Active NIH awards

• Molecular effects of metformin, PKR and TBI on C9orf72 ALS/FTD

  4R01NS098819-07

  NINDS · FY 2025 · $706K

  Project Summary The G4C2 repeat expansion mutation in the C9orf72 gene is the most common, known cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD)1,2. There are no effective treatments for C9-ALS/FTD or >50 other expansion disorders3,4. Our work identified two mechanisms now thought to play major roles in C9-ALS/FTD and other expansion diseases: 1) bidirectional transcription of expansion mutations5; and 2) repeat associated non-AUG (RAN) translation6. More than 90% of ALS presents as sporadic disease with no family history or genetic diagnosis. Surprisingly, our data show RAN proteins accumulate in ~44% of C9orf72-negative [C9(-)] sALS autopsy cases. The accumulation of toxic RAN proteins in C9(-) sALS and a growing number of other diseases highlights the need to develop drugs that block their production7-9. Activation of the integrated stress response (ISR) increases RAN translation10,11 and expansion RNAs activate the ISR kinase protein kinase R (PKR)12,13. We showed targeting RAN proteins in transgenic C9orf72 BAC mice with antibodies14 or PKR inhibition13 mitigates disease. We also discovered that metformin, a well-tolerated diabetes drug inhibits PKR, decreased RAN protein levels, improved behavior, histopathology, and motor neuron survival in C9-ALS/FTD mice13 but the mechanisms for these effects are not yet understood. These data combined with increased rates of ALS in patients with traumatic brain injury (TBI) suggest the possibility that stress and injury trigger ALS in vulnerable populations through increased RAN translation. This proposal aims to understand the mechanisms of PKR and metformin on RAN translation and to test TBI as a trigger of RAN translation and ALS that can be mitigated by PKR inhibition and metformin. In this proposal we will test the following hypothesis: (1) that metformin improves disease by reducing RAN proteins in C9orf72 ALS/FTD in a PKR dependent manner. Understanding the mechanism of action of metformin will provide important insights to advance its clinical use for C9-ALS/FTD and to improve drug efficacy; (2) that AAV-PKR-K296R is a highly effective therapeutic strategy to reduce RAN proteins in C9-ALS/FTD through p- eIF2α-dependent and independent pathways. Understanding how PKR regulates RAN translation and if AAV- PKR-K296R improves disease in adult C9-BAC mice will facilitate the development therapeutic strategies for C9orf72 ALS/FTD; and (3) that injury will increase RAN translation and exacerbate disease in C9orf72 mice and brain organoids from C9+ and genetically unknown, sporadic RAN+ sALS (gsr+ALS) patients and that reducing RAN protein levels will be protective. Taken together these innovative series of experiments could fundamentally change the diagnostics and treatment options for patients with C9-ALS, genetically unknown RAN positive sALS as well as the larger family of RAN protein associated expansions diseases. 1

• Novel repeat associated non-AUG (RAN) proteins in sALS sFTD and SBMA: shared pathological features and unifying therapeutic opportunities

  4R01NS126536-02

  NINDS · FY 2025 · $694K

  ABSTRACT Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex neurodegenerative diseases that affect motor neurons in various regions of brain and spinal cord with devastating impacts on a patient’s health and lifespan. While research has identified ALS and FTD mutations in a number of genes (i.e. C9orf72, MAPT, SOD, and GRN), approximately 90% of ALS and 60% of FTD patients present as sporadic cases (sALS & sFTD) with unknown genetic etiology. Complex disease mechanisms coupled with a large genetically and phenotypically heterogeneous patient population have severely limited research and therapeutic success for these diseases. The discovery of the intronic C9orf72 G4C2 repeat expansion mutation as the most common genetic cause of ALS and FTD links these diseases to the larger family of microsatellite expansion disorders. Amongst these diseases is spinal-bulbar muscular atrophy (SBMA), a CAG•CTG disease that, like ALS and FTD, also affects motor neurons. A growing number of expansion disorders are reported to express proteins in multiple reading frames by repeat associated non-AUG (RAN) translation. Our recent unpublished findings show that novel polySer and polyLeu RAN proteins accumulate in at least six of the ten CAG•CTG polyGln diseases. These observations raise the possibility that novel polySer and polyLeu RAN proteins accumulate in the spinal-bulbar muscular atrophy (SBMA) and that other unidentified RAN proteins may contribute to sALS and sFTD. Our central hypothesis is that repeat expansion mutations that express novel RAN proteins substantially contribute to sALS, sFTD and spinobulbar muscular atrophy (SBMA) and that therapeutic approaches that reduce RAN protein levels will improve disease in preclinical models. To address this hypothesis, we have developed an innovative pathology-to-genetics strategy that enables rapid and direct identification of novel RAN protein producing expansion mutations from patient DNA. We are excited to report that in an initial screen, ~30% of sALS autopsy cases of unknown genetic etiology (i.e. C9 and SCA36 negative) were positive for GR or PR RAN protein aggregates suggesting the presence of novel expansion mutations. In this proposal, we will test the hypothesis that novel types of RAN proteins contribute to sALS, sFTD and SBMA (Aim 1) using immunoassays and patient blood and autopsy tissue samples. In Aim 2, we will utilize an innovative dCas9READ method to identify novel repeat expansion mutations in RAN(+) sALS and sFTD cases and study the toxic effects of putative disease-causing expansion mutations. Lastly, we will test the hypothesis that decreasing RAN translation using AAV-PKR(K296R) or metformin will improve disease phenotypes in patient derived induced models and mouse models of sALS, sFTD and SBMA (Aim 3). Taken together, these studies will provide critical insights into the molecular mechanisms of sALS, sFTD and SBMA and facilitate the development of unifying therapeutic approaches to fight these devastating diseases.

• Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases

  5R01NS117910-05

  NINDS · FY 2025 · $576K

  Project Summary Since we discovered repeat associated non-ATG (RAN) RAN translation in 2011, we and others have shown that RAN proteins accumulate in nine different expansion disorders. These proteins, which can be expressed from both sense and antisense expansion transcripts, accumulate in disease-relevant human tissues including spinocerebellar ataxia type 8 (SCA8) and Huntington disease (HD). We now have evidence that polySer and polyLeu RAN proteins accumulate in a group of spinocebellar ataxias (SCA1, 2, 3, 6 and 7) in which the CAG·CTG expansion mutations are located in polyGln open reading frames. Additionally, we have developed AAV and small molecule approaches to inhibit RAN translation. We will use these tools and genetic approaches to test our central hypotheses that RAN protein pathology is a common feature shared across polyglutamine encoding CAG·CTG expansion disorders and that inhibiting the PKR pathway will reduce RAN protein levels and mitigate disease. We will address our central hypothesis in three specific aims (1) To test the hypothesis that RAN proteins contribute to spinocerebellar ataxias (SCAs) caused by polyglutamine encoding CAG·CTG repeat expansion mutations. (2) To test the hypothesis that SCA and HD RAN proteins are toxic and PKR inhibition will decrease RAN protein levels and improve cellular phenotypes in HD and SCA3 iPSC derived cells (3) : To test the hypothesis that RAN proteins contribute to HD and SCA3 phenotypes in mice independent of polyGln effects using genetic and pharmacological approaches. Taken together these specific aims will determine the contribution of RAN proteins to HD,SCA3 and CAG·CTG repeat expansion disorders and characterize PKR inhibition as a potential therapeutic approach for this large class of devastating repeat expansion diseases.

• Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases

  3R01NS117910-05S1

  NINDS · FY 2025 · $48K

  Project Summary Since we discovered repeat associated non-ATG (RAN) RAN translation in 2011, we and others have shown that RAN proteins accumulate in nine different expansion disorders. These proteins, which can be expressed from both sense and antisense expansion transcripts, accumulate in disease-relevant human tissues including spinocerebellar ataxia type 8 (SCA8) and Huntington disease (HD). We now have evidence that polySer and polyLeu RAN proteins accumulate in a group of spinocebellar ataxias (SCA1, 2, 3, 6 and 7) in which the CAG·CTG expansion mutations are located in polyGln open reading frames. Additionally, we have developed AAV and small molecule approaches to inhibit RAN translation. We will use these tools and genetic approaches to test our central hypotheses that RAN protein pathology is a common feature shared across polyglutamine encoding CAG·CTG expansion disorders and that inhibiting the PKR pathway will reduce RAN protein levels and mitigate disease. We will address our central hypothesis in three specific aims (1) To test the hypothesis that RAN proteins contribute to spinocerebellar ataxias (SCAs) caused by polyglutamine encoding CAG·CTG repeat expansion mutations. (2) To test the hypothesis that SCA and HD RAN proteins are toxic and PKR inhibition will decrease RAN protein levels and improve cellular phenotypes in HD and SCA3 iPSC derived cells (3) : To test the hypothesis that RAN proteins contribute to HD and SCA3 phenotypes in mice independent of polyGln effects using genetic and pharmacological approaches. Taken together these specific aims will determine the contribution of RAN proteins to HD,SCA3 and CAG·CTG repeat expansion disorders and characterize PKR inhibition as a potential therapeutic approach for this large class of devastating repeat expansion diseases.

Earlier awards

• 10th International Unstable Microsatellites and Human Disease MeetingFY 2025 · $10K