Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Misko, Albert L.; Ld, Weinstock; Sb, Sankar; Furness, Amanda; Grishchuk, Yulia; Lb, Wood

doi:10.1101/2021.03.16.21252395

Cited by 3 publications

(5 citation statements)

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“…Proteins were considered to correlate with Ashworth scores if there was significant correlation with at least two individual scores. Importantly, we found that the majority of the significant correlations were with age, indicating age-related "progressive" protein signature of the disease (2,26). Among all DEPs, only GABA Type A Receptor-Associated Protein (GABARAP) and S100 Calcium Binding Protein A6 (S100A6) were significantly correlated with gross motor, fine motor, and Ashworth scores (Figs 2C,D).…”

Section: Plasma Proteins In MLIV Patients Correlate With Motor Functi...mentioning

confidence: 83%

“…Motivated by our prior work showing shared cytokine changes in MLIV between human blood and mouse brain (26), we hypothesized in the current study that that we would identify blood signatures associated with the primary neuronal and lysosomal dysregulation found in the MLIV brains. Because data is limited in human MLIV brains, we compared our findings in human blood with mouse MLIV brain proteome, identifying a subset of shared changes between these compartments/species.…”

Section: Discussionmentioning

confidence: 99%

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Plasma Proteomic Signature of Mucolipidosis Type IV

Tobin,

Misko,

Miller-Browne

et al. 2024

Preprint

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Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by the loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, lysosomal abnormalities, and increased cytokine expression. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. In the current study, we analyzed 7,322 proteins in the plasma proteome and compare protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). To do so, we used aptamer-based protein profiling on plasma isolated from 18 MLIV patients and 37 aged-matched controls from a biorepository. We identified a total of 1,961 differentially expressed proteins between MLIV and control subjects, with functions spanning many major hallmarks of MLIV. Our analysis revealed a decrease in the abundance of neuronal proteins and an increase in muscle proteins, consistent with the neuronal dysfunction and muscle pathology observed in patients. In particular, lower levels of synaptic proteins (e.g., GABARAP) best correlated with disease severity. Next, we compared the plasma proteome of patients to the brain proteome from the mouse model of MLIV and identified shared alterations in 45 proteins. The up-regulated overlapping proteins were largely related to lysosomal function (e.g., ACTN2, GLB1), while the down-regulated proteins were largely related to myelination (e.g. TPPP3, CNTN2). Both signatures are consistent with our understanding of key disease hallmarks: impaired myelination and modified lysosomal function. Collectively, these data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain and suggest candidate markers relevant to MLIV pathology to be validated in future studies.

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Section: Plasma Proteins In MLIV Patients Correlate With Motor Functi...mentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Plasma Proteomic Signature of Mucolipidosis Type IV

Tobin,

Misko,

Miller-Browne

et al. 2024

Preprint

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“…Although mild phenotypic variants of MLIV have been described, formal nomenclature and classification criteria have not been established. 1 Based on the authors' combined experience with the MLIV population, patients were classified as mild if they had achieved independent ambulation at any point in life. The remaining 23 patients were classified as typical.…”

Section: Resultsmentioning

confidence: 99%

“…Mucolipidosis type IV (MLIV) is an inherited lysosomal disorder characterized by hypomyelination, severe neurodevelopmental delay, progressive visual impairment, and achlorhydria. 1 The true prevalence is unknown, but MLIV is considered an ultra-rare condition with approximately 100 identified patients worldwide (personal communication from the ML4 Foundation). 2 - 4 Low patient numbers limit our understanding of the natural history of disease, but early cohort studies have provided seminal data on the phenotypic spectrum of MLIV, 5 - 7 and severe (typical) and mild (atypical) forms have been described.…”

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confidence: 99%

Cross-sectional Observations on the Natural History of Mucolipidosis Type IV

et al. 2022

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Background and ObjectivesMucolipidosis type IV (MLIV) is an ultra-rare lysosomal disorder initially described as a static neurodevelopmental condition. However, patient caregivers frequently report progressive muscular hypertonicity and functional decline. We evaluated a cohort of patients with MLIV to determine whether neurologic disability correlates with age.MethodsWe performed a cross-sectional, observational study of 26 patients with MLIV in the United States and Israel ranging in age from 2 to 40 years. Medical history was obtained from caregivers, and patients underwent a full neurologic examination. The Brief Assessment of Motor Function (BAMF), Gross Motor Function Classification System, and modified Ashworth scales were applied. Caregivers identified developmental skills on the Oregon Project for Visually Impaired and Blind Children checklist that their child had lost the ability to perform.ResultsThree patients were clinically classified as mildly affected and the remaining 23 patients as typical, severely affected cases. Timing of first symptom onset ranged from 1.5 months to 8 years of age (median 7.25 months). Across typical patients, modified Ashworth scores demonstrated a positive age dependence illustrating worsening spasticity across the lifespan. Signs of extrapyramidal motor dysfunction were also qualitatively observed. In parallel, gross and fine motor function assessed with the BAMF and Gross Motor Function Classification System scales declined across age. All typical patients had restricted tongue mobility and lacked rotary jaw movement when chewing, but BAMF scores for deglutition declined only in the oldest patients. In contrast, scores for articulation were low in all patients and did not correlate with age. Finally, loss of developmental skills frequently occurred in early adolescence.DiscussionThis cross-sectional natural history study of MLIV demonstrates worse motor function in older patients. These data support a neurodegenerative component of MLIV that manifests as developmental regression in the second decade of life. Whether the emergence of functional decline results from the cumulative, nonlinear interactions of steadily progressive neurodegenerative processes or reflects an inflection from impaired CNS development to degeneration is uncertain. However, understanding the relationship between CNS pathology and clinical course of disease will be imperative to guiding future interventional trials and optimizing patient care.

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“…Most of the known patients with MLIV exhibit the typical severe form, which is associated with variants that completely abolish TRPML1 function or prevent its production (Misko et al, 1993;Altarescu et al, 2002). Therefore, conventional knockout of Mcoln1 presents a relevant approach to create preclinical model of this disease.…”

Section: Introductionmentioning

confidence: 99%

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

Sangster

Shahriar²,

Niziolek

et al. 2023

Front. Mol. Neurosci.

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Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS) and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness, and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently, there are no approved or investigational therapies for MLIV, and pathogenic mechanisms remain largely unknown. The MLIV mouse model, Mcoln1−/− mice, recapitulates all major manifestations of the human disease. Here, to better understand the pathological mechanisms in the MLIV brain, we performed cell type specific LC–MS/MS proteomics analysis in the MLIV mouse model and reconstituted molecular signatures of the disease in either freshly isolated populations of neurons, astrocytes, oligodendrocytes, and neural stem cells, or whole tissue cortical homogenates from young adult symptomatic Mcoln1−/− mice. Our analysis confirmed on the molecular level major histopathological hallmarks of MLIV universally present in Mcoln1−/− tissue and brain cells, such as hypomyelination, lysosomal dysregulation, and impaired metabolism of lipids and polysaccharides. Importantly, pathway analysis in brain cells revealed mitochondria-related alterations in all Mcoln1−/− brain cells, except oligodendrocytes, that was not possible to resolve in whole tissue. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease.

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Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Cited by 3 publications

References 68 publications

Plasma Proteomic Signature of Mucolipidosis Type IV

Plasma Proteomic Signature of Mucolipidosis Type IV

Cross-sectional Observations on the Natural History of Mucolipidosis Type IV

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

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