Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

Gittings, Lauren M.; Sattler, Rita

doi:10.12703/b/9-12

Cited by 21 publications

(11 citation statements)

References 158 publications

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“…Most cases are sporadic, with only 15% of cases caused by known genetic mutations. Riluzole, edaravone, and comprehensive patient care are the only available interventions for ALS and only marginally improve patient survival (Gittings and Sattler, 2020). The unknown disease etiology and lack of sensitive diagnostic and prognostic biomarkers present a challenge for drug development.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Figueroa‐Romero

Hur

et al. 2021

Front. Mol. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a terminalneurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles (EVs) transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n = 15) and healthy control (n = 16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.

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Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Figueroa‐Romero

Hur

et al. 2021

Front. Mol. Neurosci.

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“…Processes explaining the mechanisms behind motoneuron degeneration in ALS and SMA are not fully understood. 1 , 4 , 48 However, several mechanisms have been described and factors either associated with or being modified of the diseases have been identified. While SMA is a monogenic disease, 21 ALS is caused by different factors.…”

Section: Discussionmentioning

confidence: 99%

“… 1 In ALS and SMA, alterations in actin dynamics, inflammatory responses as well as altered signaling pathways have been described as such central molecular mechanisms (see reviews 1 - 3 ). 1 - 5 …”

Section: Introductionmentioning

confidence: 99%

Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA

Kubinski

Claus²

2022

J Exp Neurosci

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Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases which are characterized by the loss of motoneurons within the central nervous system. SMA is a monogenic disease caused by reduced levels of the Survival of motoneuron protein, whereas ALS is a multi-genic disease with over 50 identified disease-causing genes and involvement of environmental risk factors. Although these diseases have different causes, they partially share identical phenotypes and pathomechanisms. To analyze and identify functional connections and to get a global overview of altered pathways in both diseases, protein network analyses are commonly used. Here, we used an in silico tool to test for functional associations between proteins that are involved in actin cytoskeleton dynamics, fatty acid metabolism, skeletal muscle metabolism, stress granule dynamics as well as SMA or ALS risk factors, respectively. In network biology, interactions are represented by edges which connect proteins (nodes). Our approach showed that only a few edges are necessary to present a complex protein network of different biological processes. Moreover, Superoxide dismutase 1, which is mutated in ALS, and the actin-binding protein profilin1 play a central role in the connectivity of the aforementioned pathways. Our network indicates functional links between altered processes that are described in either ALS or SMA. These links may not have been considered in the past but represent putative targets to restore altered processes and reveal overlapping pathomechanisms in both diseases.

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“…Although there are data suggesting positive effects of several substances on the clinical course of ALS, riluzole and edaravone remain the only FDA approved drugs against this disease [ 19 – 21 ]. Patient Internet forums and websites, such as “Patients like me” [ 22 ], suggest possible off-label medications against ALS.…”

Section: Introductionmentioning

confidence: 99%

Use of Off-Label Drugs and Nutrition Supplements among Patients with Amyotrophic Lateral Sclerosis in Norway

Johanson

Tysnes

Bjerknes

2022

Neurology Research International

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Background and Objectives. Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, characterized by gradual paralysis and muscle atrophy. Riluzole, the only approved treatment in Norway, increases mean survival by 3–6 months. The use of off-label medications and nutritional supplements is common in other serious conditions, such as Parkinson’s disease and dementia. The aims of this study were to investigate to what extent Norwegian ALS patients use supplements and off-label medications and whether this is related to their health-related quality-of-life (HRQOL). Materials and Methods. A cross-sectional questionnaire study was performed, where 41 ALS patients reported their use of off-label treatments, as well as self-perceived HRQOL using the RAND-12 questionnaire. Results. A majority of respondents used riluzole. Of the 41 respondents, 18 (43.9%) reported use of off-label medications and 18 (43.9%) used nutritional supplements. Low-dose naltrexone was the most commonly used off-label medication, whereas vitamins accounted for most of the nutritional supplements. The respondents’ RAND-12 component scores were significantly lower than those of the general population. Low-dose naltrexone and vitamin B were associated with a better physical component score. Conclusions. Most of the respondents in our study adhere to the recommended treatment protocols, as less than half of them reported using off-label medications or nutritional supplements against ALS. Positive correlations between physical HRQOL and use of low-dose naltrexone or vitamin B were demonstrated. These results warrant further investigations.

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Recent advances in understanding amyotrophic lateral sclerosis and emerging therapies

Cited by 21 publications

References 158 publications

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA

Use of Off-Label Drugs and Nutrition Supplements among Patients with Amyotrophic Lateral Sclerosis in Norway

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