Desiree M. Baron

University of Massachusetts Chan Medical School

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John E. Landers

University of Massachusetts Chan Medical School

Daryl A. Bosco

University of Massachusetts Chan Medical School

Claudia Fallini

University of Rhode Island

Katherine V. Gall

University of Massachusetts Chan Medical School

Pamela Keagle

University of Massachusetts Chan Medical School

Maeve Tischbein

Vanderbilt University Medical Center

Yen‐Chen Lin

National Yang Ming Chiao Tung University

Zakayi Kabututu

University of California, Los Angeles

Stephen Doxsey

University of Massachusetts Chan Medical School

JeanMarie Houghton

Unilever (United Kingdom)

Cooperative Institutions

University of Massachusetts Chan Medical School

Harvard University

Northwestern University

Howard Hughes Medical Institute

Massachusetts General Hospital

Istituti di Ricovero e Cura a Carattere Scientifico

University Medical Center Utrecht

Utrecht University

University of Milan

Massachusetts Institute of Technology

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Stuck in reverse: loss of LC1 inTrypanosoma bruceidisrupts outer dynein arms and leads to reverse flagellar beat and backward movement

Journal of Cell Science (2007)

Desiree M. Baron Zakayi Kabututu Kent L. Hill

Axonemal dyneins are multisubunit molecular motors that provide the driving force for flagellar motility. Dynein light chain 1 (LC1) has been well studied in Chlamydomonas reinhardtii and is unique among all dynein components as the only protein known to bind directly to the catalytic motor domain of the dynein heavy chain. However, the role of LC1 in dynein assembly and/or function is unknown because no mutants have previously been available. We identified an LC1 homologue (TbLC1) in Trypanosoma brucei and have investigated its role in trypanosome flagellar motility using epitope tagging and RNAi studies. TbLC1 is localized along the length of the flagellum and partitions between the axoneme and soluble fractions following detergent and salt extraction. RNAi silencing of TbLC1 gene expression results in the complete loss of the dominant tip-to-base beat that is a hallmark of trypanosome flagellar motility and the concomitant emergence of a sustained reverse beat that propagates base-to-tip and drives cell movement in reverse. Ultrastructure analysis revealed that outer arm dyneins are disrupted in TbLC1 mutants. Therefore LC1 is required for stable dynein assembly and forward motility in T. brucei. Our work provides the first functional analysis of LC1 in any organism. Together with the recent findings in T. brucei DNAI1 mutants [Branche et al. (2006). Conserved and specific functions of axoneme components in trypanosome motility. J. Cell Sci. 119, 3443-3455], our data indicate functionally specialized roles for outer arm dyneins in T. brucei and C. reinhardtii. Understanding these differences will provide a more robust description of the fundamental mechanisms underlying flagellar motility and will aid efforts to exploit the trypanosome flagellum as a drug target.

Axoneme

Chlamydomonas

Dynein ATPase

10.1242/jcs.004846

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Citations (82)

Erratum: Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity

Nature Cell Biology (2011)

Tse-Chun Kuo Chun‐Ting Chen Desiree M. Baron Tamer T. Önder Sabine Loewer

Reprogramming

Evasion (ethics)

Nat

Section (typography)

10.1038/ncb2405

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Citations (6)

The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing

Journal of Biological Chemistry (2019)

Maeve Tischbein Desiree M. Baron Yen‐Chen Lin Katherine V. Gall John E. Landers

Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in nucleocytoplasmic transport. Furthermore, glutamate-induced up-regulation of glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type subunit 2 (GRIA2) in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely excitotoxicity, disease-associated RBPs, and nucleocytoplasmic transport.

Excitotoxicity

10.1074/jbc.ra118.005933

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Citations (23)

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease

Nature Genetics (2024)

Paul J. Hop Dongbing Lai Pamela Keagle Desiree M. Baron Brendan Kenna

Abstract Despite substantial progress, causal variants are identified only for a minority of familial Parkinson’s disease (PD) cases, leaving high-risk pathogenic variants unidentified 1,2 . To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs. 3,4 ). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD—LRRK2 kinase activity 5–7 —and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.

10.1038/s41588-024-01787-7

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Citations (21)

FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for Gria2 mRNA processing

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Maeve Tischbein Desiree M. Baron Yen‐Chen Lin Katherine V. Gall John E. Landers

Abstract Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function and pathology have not been explored. Here, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity include TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS translocation occurs through a calcium-dependent mechanism and coincides with striking alterations in nucleocytoplasmic transport. Further, glutamate-induced upregulation of Gria2 in neurons was dependent on FUS expression, consistent with a functional role for FUS under excitotoxic stress. These findings reveal a link between prominent factors in neurodegenerative disease, namely excitotoxicity, disease-associated RBPs and nucleocytoplasmic transport.

Excitotoxicity

Stress granule

10.1101/386870

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Citations (0)

ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function

Cell Reports (2022)

Desiree M. Baron Adam R. Fenton Sara Sáez-Atiénzar Anthony Giampetruzzi Aparna Sreeram

Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.

Gain of function

10.1016/j.celrep.2022.110598

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Citations (66)

Functional genomics inTrypanosoma bruceiidentifies evolutionarily conserved components of motile flagella

Journal of Cell Science (2007)

Desiree M. Baron Katherine S. Ralston Zakayi Kabututu Kent L. Hill

Cilia and flagella are highly conserved, complex organelles involved in a variety of important functions. Flagella are required for motility of several human pathogens and ciliary defects lead to a variety of fatal and debilitating human diseases. Many of the major structural components of cilia and flagella are known, but little is known about regulation of flagellar beat. Trypanosoma brucei, the causative agent of African sleeping sickness, provides an excellent model for studying flagellar motility. We have used comparative genomics to identify a core group of 50 genes unique to organisms with motile flagella. These genes, referred to as T. brucei components of motile flagella (TbCMF) include 30 novel genes, and human homologues of many of the TbCMF genes map to loci associated with human ciliary diseases. To characterize TbCMF protein function we used RNA interference to target 41 TbCMF genes. Sedimentation assays and direct observation demonstrated clear motility defects in a majority of these knockdown mutants. Epitope tagging, fluorescence localization and biochemical fractionation demonstrated flagellar localization for several TbCMF proteins. Finally, ultrastructural analysis identified a family of novel TbCMF proteins that function to maintain connections between outer doublet microtubules, suggesting that they are the first identified components of nexin links. Overall, our results provide insights into the workings of the eukaryotic flagellum, identify several novel human disease gene candidates, reveal unique aspects of the trypanosome flagellum and underscore the value of T. brucei as an experimental system for studying flagellar biology.

Intraflagellar Transport

Motile cilium

Model Organism

10.1242/jcs.03352

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Citations (100)

Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS

Human Molecular Genetics (2019)

Desiree M. Baron Tyler Matheny Yen‐Chen Lin John Leszyk Kevin P. Kenna

Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses in neurodegeneration. However, our knowledge of the proteins that evade translational repression is incomplete. It is also unclear whether disease-linked proteins influence the proteome under conditions of translational repression. To address these questions, a quantitative proteomics approach was used to identify proteins that evade stress-induced translational repression in arsenite-treated cells expressing either wild-type or amyotrophic lateral sclerosis (ALS)-linked mutant FUS. This study revealed hundreds of proteins that are actively synthesized during stress-induced translational repression, irrespective of FUS genotype. In addition to proteins involved in RNA- and protein-processing, proteins associated with neurodegenerative diseases such as ALS were also actively synthesized during stress. Protein synthesis under stress was largely unperturbed by mutant FUS, although several proteins were found to be differentially expressed between mutant and control cells. One protein in particular, COPBI, was downregulated in mutant FUS-expressing cells under stress. COPBI is the beta subunit of the coat protein I (COPI), which is involved in Golgi to endoplasmic reticulum (ER) retrograde transport. Further investigation revealed reduced levels of other COPI subunit proteins and defects in COPBI-relatedprocesses in cells expressing mutant FUS. Even in the absence of stress, COPBI localization was altered in primary and human stem cell-derived neurons expressing ALS-linked FUS variants. Our results suggest that Golgi to ER retrograde transport may be important under conditions of stress and is perturbed upon the expression of disease-linked proteins such as FUS.

Stress granule

Proteome

COPI

Translational regulation

10.1093/hmg/ddz048

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Citations (18)

Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics

Molecular Neurodegeneration (2013)

Desiree M. Baron Laura J. Kaushansky Catherine L. Ward Reddy Ranjith K. Sama Ru-Ju Chian

Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Since only the mutants, but not the endogenous wild-type FUS, are associated with stress granules under most of the stress conditions reported to date, the relationship between FUS and stress granules represents a mutant-specific phenotype and thus may be of significance in mutant-induced pathogenesis. While the association of mutant-FUS with stress granules is well established, the effect of the mutant protein on stress granules has not been examined. Here we investigated the effect of mutant-FUS on stress granule formation and dynamics under conditions of oxidative stress.We found that expression of mutant-FUS delays the assembly of stress granules. However, once stress granules containing mutant-FUS are formed, they are more dynamic, larger and more abundant compared to stress granules lacking FUS. Once stress is removed, stress granules disassemble more rapidly in cells expressing mutant-FUS. These effects directly correlate with the degree of mutant-FUS cytoplasmic localization, which is induced by mutations in the nuclear localization signal of the protein. We also determine that the RGG domains within FUS play a key role in its association to stress granules. While there has been speculation that arginine methylation within these RGG domains modulates the incorporation of FUS into stress granules, our results demonstrate that this post-translational modification is not involved.Our results indicate that mutant-FUS alters the dynamic properties of stress granules, which is consistent with a gain-of-toxic mechanism for mutant-FUS in stress granule assembly and cellular stress response.

Stress granule

Granule (geology)

10.1186/1750-1326-8-30

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Citations (136)

Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import

Science Advances (2023)

Jacob R. Mann Elizabeth D. McKenna Darilang Mawrie Vasileios Papakis Francesco Alessandrini

Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-β1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in Drosophila models in vivo, while using several induced pluripotent stem cell (iPSC)–MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate.

Genetic screen

10.1126/sciadv.adi5548

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Citations (15)