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From animal models to human disease: a genetic approach for personalized medicine in ALS.

Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N - Acta Neuropathol Commun (2016)

Bottom Line: Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others.However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans.Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuroscience, Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. vincent.picher-martel.1@ulaval.ca.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

No MeSH data available.


Related in: MedlinePlus

Neuropathological findings in human sALS cases and animal models of ALS. Microscopic pictures of neuropathological findings in ALS models. Our previously published TDP-43 and SOD1 mouse models were exploited for illustration of TDP-43 and SOD1 aggregates with permission. a Immunofluorescence microscopy of a hSOD1G93A mouse spinal cord. The B8H10 antibody was utilized for the specific signal of misfolded SOD1. Pictures were taken at 10x and b 40x magnification for better visualization of aggregates. c-e Double immunofluorescence microscopy of 10 months-old a hTDP-43G348C mouse spinal cord using hTDP-43 monoclonal antibody and d ubiquitin antibody [138]. Ubiquinated TDP-43 cytoplasmic aggregates can be observed and are typical neuropathological findings in human ALS. f-i Immunofluorescence of 10 months-old hTDP-43G348C and non-transgenic mice spinal cord. Iba1 antibody f-g and GFAP antibody h-i showed increased microgliosis and astrogliosis in a 10 months-old hTDP-43G348C mouse. j-l Immunohistochemistry of two human sporadic ALS cases using TDP-43 antibody to illustrated typical neuronal cytoplasmic TDP-43 inclusions in lumbar spinal cord (j), medulla (k) and motor cortex (l). Scale bar = 250 μm (a); 50 μm (b, f-i); 25 μm (c-e); 100 μm (j-l)
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Fig3: Neuropathological findings in human sALS cases and animal models of ALS. Microscopic pictures of neuropathological findings in ALS models. Our previously published TDP-43 and SOD1 mouse models were exploited for illustration of TDP-43 and SOD1 aggregates with permission. a Immunofluorescence microscopy of a hSOD1G93A mouse spinal cord. The B8H10 antibody was utilized for the specific signal of misfolded SOD1. Pictures were taken at 10x and b 40x magnification for better visualization of aggregates. c-e Double immunofluorescence microscopy of 10 months-old a hTDP-43G348C mouse spinal cord using hTDP-43 monoclonal antibody and d ubiquitin antibody [138]. Ubiquinated TDP-43 cytoplasmic aggregates can be observed and are typical neuropathological findings in human ALS. f-i Immunofluorescence of 10 months-old hTDP-43G348C and non-transgenic mice spinal cord. Iba1 antibody f-g and GFAP antibody h-i showed increased microgliosis and astrogliosis in a 10 months-old hTDP-43G348C mouse. j-l Immunohistochemistry of two human sporadic ALS cases using TDP-43 antibody to illustrated typical neuronal cytoplasmic TDP-43 inclusions in lumbar spinal cord (j), medulla (k) and motor cortex (l). Scale bar = 250 μm (a); 50 μm (b, f-i); 25 μm (c-e); 100 μm (j-l)

Mentions: Numerous SOD1 mouse models have been created and they have variable phenotypes, age of disease onset and survival (Table 3). These heterogeneous phenotypes seems to be dependent on specific mutations, expression levels of mutant SOD1, gender and genetic background [72]. Generally, females experienced delayed onset and prolonged survival as compared to males and such differences can also be observed in humans [73]. Most SOD1 mutant mice represent human SOD1 pathology quite well. Mice develop fatal paralysis with motor neuron deficit, gliosis and intracytoplasmic ubiquitinated SOD1 inclusions (Fig. 3). However, poor correlation can be made between age of onset and progression in mouse and human. For example, the A4V mutation, the most frequent mutation in humans which causes a rapid disease, is not pathogenic in mouse before 85 weeks [74]. Moreover, the SOD1 G93A mutation, which leads to an early onset and fast progression in mouse, has a slow rate of progression in human (Tables 1 and 2). Interestingly, the D90A mutation in mice and humans shows strong similarities. Homozygous SOD1D90A mice exhibit a slow disease progression and bladder disturbance, which are also found in humans with the same homozygous mutation [45, 75]. Cognitive symptoms have been described in some mouse models. Mice exhibiting the G37R mutation have learning deficits in passive avoidance from 8 months of age and pre-symptomatic SOD1G93A mice exhibit learning delay and long-term memory deficits [76, 77]. Non-motor features such as sensory deficits are described in G37R and D83G [78].Fig. 3


From animal models to human disease: a genetic approach for personalized medicine in ALS.

Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupré N - Acta Neuropathol Commun (2016)

Neuropathological findings in human sALS cases and animal models of ALS. Microscopic pictures of neuropathological findings in ALS models. Our previously published TDP-43 and SOD1 mouse models were exploited for illustration of TDP-43 and SOD1 aggregates with permission. a Immunofluorescence microscopy of a hSOD1G93A mouse spinal cord. The B8H10 antibody was utilized for the specific signal of misfolded SOD1. Pictures were taken at 10x and b 40x magnification for better visualization of aggregates. c-e Double immunofluorescence microscopy of 10 months-old a hTDP-43G348C mouse spinal cord using hTDP-43 monoclonal antibody and d ubiquitin antibody [138]. Ubiquinated TDP-43 cytoplasmic aggregates can be observed and are typical neuropathological findings in human ALS. f-i Immunofluorescence of 10 months-old hTDP-43G348C and non-transgenic mice spinal cord. Iba1 antibody f-g and GFAP antibody h-i showed increased microgliosis and astrogliosis in a 10 months-old hTDP-43G348C mouse. j-l Immunohistochemistry of two human sporadic ALS cases using TDP-43 antibody to illustrated typical neuronal cytoplasmic TDP-43 inclusions in lumbar spinal cord (j), medulla (k) and motor cortex (l). Scale bar = 250 μm (a); 50 μm (b, f-i); 25 μm (c-e); 100 μm (j-l)
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Related In: Results  -  Collection

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Fig3: Neuropathological findings in human sALS cases and animal models of ALS. Microscopic pictures of neuropathological findings in ALS models. Our previously published TDP-43 and SOD1 mouse models were exploited for illustration of TDP-43 and SOD1 aggregates with permission. a Immunofluorescence microscopy of a hSOD1G93A mouse spinal cord. The B8H10 antibody was utilized for the specific signal of misfolded SOD1. Pictures were taken at 10x and b 40x magnification for better visualization of aggregates. c-e Double immunofluorescence microscopy of 10 months-old a hTDP-43G348C mouse spinal cord using hTDP-43 monoclonal antibody and d ubiquitin antibody [138]. Ubiquinated TDP-43 cytoplasmic aggregates can be observed and are typical neuropathological findings in human ALS. f-i Immunofluorescence of 10 months-old hTDP-43G348C and non-transgenic mice spinal cord. Iba1 antibody f-g and GFAP antibody h-i showed increased microgliosis and astrogliosis in a 10 months-old hTDP-43G348C mouse. j-l Immunohistochemistry of two human sporadic ALS cases using TDP-43 antibody to illustrated typical neuronal cytoplasmic TDP-43 inclusions in lumbar spinal cord (j), medulla (k) and motor cortex (l). Scale bar = 250 μm (a); 50 μm (b, f-i); 25 μm (c-e); 100 μm (j-l)
Mentions: Numerous SOD1 mouse models have been created and they have variable phenotypes, age of disease onset and survival (Table 3). These heterogeneous phenotypes seems to be dependent on specific mutations, expression levels of mutant SOD1, gender and genetic background [72]. Generally, females experienced delayed onset and prolonged survival as compared to males and such differences can also be observed in humans [73]. Most SOD1 mutant mice represent human SOD1 pathology quite well. Mice develop fatal paralysis with motor neuron deficit, gliosis and intracytoplasmic ubiquitinated SOD1 inclusions (Fig. 3). However, poor correlation can be made between age of onset and progression in mouse and human. For example, the A4V mutation, the most frequent mutation in humans which causes a rapid disease, is not pathogenic in mouse before 85 weeks [74]. Moreover, the SOD1 G93A mutation, which leads to an early onset and fast progression in mouse, has a slow rate of progression in human (Tables 1 and 2). Interestingly, the D90A mutation in mice and humans shows strong similarities. Homozygous SOD1D90A mice exhibit a slow disease progression and bladder disturbance, which are also found in humans with the same homozygous mutation [45, 75]. Cognitive symptoms have been described in some mouse models. Mice exhibiting the G37R mutation have learning deficits in passive avoidance from 8 months of age and pre-symptomatic SOD1G93A mice exhibit learning delay and long-term memory deficits [76, 77]. Non-motor features such as sensory deficits are described in G37R and D83G [78].Fig. 3

Bottom Line: Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others.However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans.Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuroscience, Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. vincent.picher-martel.1@ulaval.ca.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

No MeSH data available.


Related in: MedlinePlus