Meaghan Van Alstyne

Columbia University

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Livio Pellizzoni

Columbia University

George Z. Mentis

Columbia University

Christian M. Simon

Leipzig University

Francesco Lotti

Columbia University Irving Medical Center

Sarah Tisdale

Columbia University

Elena Bianchetti

Columbia University

Joshua I. Chalif

Brigham and Women's Hospital

Lamya S. Shihabuddin

Sanofi (United States)

John G. Pagiazitis

Columbia University

Joseph E. Rabinowitz

Temple University

Cooperative Institutions

Columbia University

Columbia University Irving Medical Center

University of Colorado Boulder

Howard Hughes Medical Institute

University of Southern California

University of Colorado System

National Institute of Neurological Disorders and Stroke

National Institutes of Health

Brigham and Women's Hospital

Wright State University

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Stasimon/Tmem41b is required for cell proliferation and adult mouse survival

Biochemical and Biophysical Research Communications (2024)

María J. Carlini Meaghan Van Alstyne Hua Yang Shubhi Yadav Neil A. Shneider

Cre recombinase

Conditional gene knockout

Knockout mouse

Null allele

Gene knockin

10.1016/j.bbrc.2024.149923

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Citations (1)

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

Cell Reports (2019)

Christian M. Simon Meaghan Van Alstyne Francesco Lotti Elena Bianchetti Sarah Tisdale

Reduced expression of the survival motor neuron (SMN) protein causes the neurodegenerative disease spinal muscular atrophy (SMA). Here, we show that adeno-associated virus serotype 9 (AAV9)-mediated delivery of Stasimon—a gene encoding an endoplasmic reticulum (ER)-resident transmembrane protein regulated by SMN—improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In motor neurons, Stasimon suppresses neurodegeneration by reducing phosphorylation of the tumor suppressor p53. Moreover, Stasimon deficiency converges on SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53 through activation of p38 mitogen-activated protein kinase (MAPK), and pharmacological inhibition of this kinase prevents motor neuron death in SMA mice. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of distinct cellular cascades that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.

10.1016/j.celrep.2019.11.058

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Citations (48)

Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons

JCI Insight (2020)

Erkan Y. Osman Meaghan Van Alstyne Pei–Fen Yen Francesco Lotti Zhihua Feng

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. SMN has key functions in multiple RNA pathways, including the biogenesis of small nuclear ribonucleoproteins that are essential components of both major (U2-dependent) and minor (U12-dependent) spliceosomes. Here we investigated the specific contribution of U12 splicing dysfunction to SMA pathology through selective restoration of this RNA pathway in mouse models of varying phenotypic severity. We show that virus-mediated delivery of minor snRNA genes specifically improves select U12 splicing defects induced by SMN deficiency in cultured mammalian cells, as well as in the spinal cord and dorsal root ganglia of SMA mice without increasing SMN expression. This approach resulted in a moderate amelioration of several parameters of the disease phenotype in SMA mice, including survival, weight gain, and motor function. Importantly, minor snRNA gene delivery improved aberrant splicing of the U12 intron-containing gene Stasimon and rescued the severe loss of proprioceptive sensory synapses on SMA motor neurons, which are early signatures of motor circuit dysfunction in mouse models. Taken together, these findings establish the direct contribution of U12 splicing dysfunction to synaptic deafferentation and motor circuit pathology in SMA.

Proprioception

Small nuclear RNA

10.1172/jci.insight.130574

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Citations (20)

RNA mediated mechanisms of motor neuron death and dysfunction in SMA

Meaghan Van Alstyne

10.7916/d8-8x9m-f862

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Citations (0)

Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy

Genes & Development (2018)

Meaghan Van Alstyne Christian M. Simon S. Pablo Sardi Lamya S. Shihabuddin George Z. Mentis

Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons—a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)—through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing of Mdm2 and Mdm4, two nonredundant repressors of p53. Decreased inclusion of critical Mdm2 and Mdm4 exons is most prominent in SMA motor neurons and correlates with both snRNP reduction and p53 activation in vivo. Importantly, increased skipping of Mdm2 and Mdm4 exons regulated by SMN is necessary and sufficient to synergistically elicit robust p53 activation in wild-type mice. Conversely, restoration of full-length Mdm2 and Mdm4 suppresses p53 induction and motor neuron degeneration in SMA mice. These findings reveal that loss of SMN-dependent regulation of Mdm2 and Mdm4 alternative splicing underlies p53-mediated death of motor neurons in SMA, establishing a causal link between snRNP dysfunction and neurodegeneration.

snRNP

SMN1

Small nuclear ribonucleoprotein

10.1101/gad.316059.118

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Citations (61)

Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development

Biochemical and Biophysical Research Communications (2018)

Meaghan Van Alstyne Francesco Lotti Andrea Dal Mas Estela Area‐Gómez Livio Pellizzoni

10.1016/j.bbrc.2018.10.073

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Citations (38)

Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit

Nature Neuroscience (2021)

Meaghan Van Alstyne Ivan Tattoli Nicolas Delestrée Yocelyn Recinos Eileen Workman

Gain of function

10.1038/s41593-021-00827-3

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Citations (145)

Polyserine peptides are toxic and exacerbate tau pathology in mice

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Meaghan Van Alstyne Vanessa L. Nguyen Charles A. Hoeffer Roy Parker

Polyserine domains mediate the association of nuclear RNA binding proteins with cytoplasmic tau aggregates that occurs across tauopathy models and patient samples. In cell lines, polyserine peptides co-localize with and promote formation of tau aggregates suggesting the cytoplasmic mislocalization of polyserine-containing proteins might contribute to human disease. Moreover, polyserine can be produced by repeat associated non-AUG translation in CAG repeat expansion diseases. However, whether polyserine expressed in a mammalian brain is toxic and/or can exacerbate tau pathology is unknown. Here, we used AAV9-mediated delivery to express a 42-repeat polyserine protein in wild-type and tau transgenic mouse models. We observe that polyserine expression has toxic effects in wild-type animals indicated by reduced weight, behavioral abnormalities and a striking loss of Purkinje cells. Moreover, in the presence of a pathogenic variant of human tau, polyserine exacerbates disease markers such as phosphorylated and insoluble tau levels and the seeding capacity of brain extracts. These findings demonstrate that polyserine domains can promote tau-mediated pathology in a mouse model and are consistent with the hypothesis that cytoplasmic mislocalization of polyserine containing proteins might contribute to the progression of human tauopathies.

Tauopathy

Tau Pathology

Tau protein

10.1101/2024.10.10.616100

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Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

Cell Reports (2017)

Christian M. Simon Ya Dai Meaghan Van Alstyne Charalampia Koutsioumpa John G. Pagiazitis

Highlights•SMN deficiency induces early p53 activation in vulnerable SMA motor neurons•Inhibition of p53 prevents motor neuron degeneration in SMA mice•p53S18 phosphorylation selectively marks degenerating SMA motor neurons•Amino-terminal phosphorylation of p53 is required for motor neuron degenerationSummaryThe hallmark of spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons.Graphical abstract

Degeneration (medical)

10.1016/j.celrep.2017.12.003

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Citations (96)

Synaptic imbalance and increased inhibition impair motor function in SMA

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Emily V. Fletcher Joshua I. Chalif Travis M. Rotterman John G. Pagiazitis Meaghan Van Alstyne

Movement is executed through the balanced action of excitatory and inhibitory neurotransmission in motor circuits of the spinal cord. Short-term perturbations in one of the two types of transmission are counteracted by homeostatic changes of the opposing type. Prolonged failure to balance excitatory and inhibitory drive results in dysfunction at the single neuron, as well as neuronal network levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used mouse genetics, functional assays, morphological methods, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition neurotransmission in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable motor circuits in the SMA spinal cord fail to respond homeostatically to the reduction of excitatory drive and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment to activate muscle contraction. Importantly, genetic or pharmacological reduction of inhibitory synaptic drive improves neuronal function and provides behavioural benefit in SMA mice. Our findings identify the lack of excitation-inhibition homeostasis as a major maladaptive mechanism in SMA, by which the combined effects of reduced excitation and increased inhibition diminish the capacity of premotor commands to recruit motor neurons and elicit muscle contractions.

10.1101/2024.08.30.610545

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