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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

Timeline of gene discovery and pathogenic mechanisms in ALS. Schematic representation of years of discovery of most important genes implicated in ALS. Mutation in the superoxide dismutase 1 (SOD1) represent approximately 15 % of familial ALS cases (fALS), mutation in C9orf72 represent 35-40 % and both TAR-DNA-binding protein (TARDBP) and Fused in sarcoma (FUS) for 4 % each. Other genes represent less than 1 % each. Protein aggregation and gliosis are pathological hallmark of ALS and have been discovered before the beginning of the illustrated timeline. ER endoplasmic reticulum; NEFH neurofilament heavy; ALS2 alsin; DCTN1 dynactin; PRPH peripherin; SETX senataxin; VAPB vesicle-associated membrane protein-associated protein B; CHMP2B Charged multivesicular body protein 2B; ANG angiogenin; FIG4 phosphoinositide 5-phosphatase; OPTN optineurin; ATXN2 ataxin 2; DAO D-amino acid oxidase; SPG11 spastic paraplegia 11; VCP valosin containing protein; SIGMAR1 sigma non-opioid intracellular receptor 1; TAF15 TATA-box binding protein associated factor 15; UBQLN2 ubiquilin-2; SQSTM1 sequestosome 1; PFN1 profilin-1; HNRNPA1 heterogeneous nuclear ribonucleoprotein A1; ERBB4 erb-2 receptor tyrosine kinase 4; MATR3 matrin 3; TUBA4A tubulin alpha-4a; TBK1 TANK-binding kinase 1
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Fig1: Timeline of gene discovery and pathogenic mechanisms in ALS. Schematic representation of years of discovery of most important genes implicated in ALS. Mutation in the superoxide dismutase 1 (SOD1) represent approximately 15 % of familial ALS cases (fALS), mutation in C9orf72 represent 35-40 % and both TAR-DNA-binding protein (TARDBP) and Fused in sarcoma (FUS) for 4 % each. Other genes represent less than 1 % each. Protein aggregation and gliosis are pathological hallmark of ALS and have been discovered before the beginning of the illustrated timeline. ER endoplasmic reticulum; NEFH neurofilament heavy; ALS2 alsin; DCTN1 dynactin; PRPH peripherin; SETX senataxin; VAPB vesicle-associated membrane protein-associated protein B; CHMP2B Charged multivesicular body protein 2B; ANG angiogenin; FIG4 phosphoinositide 5-phosphatase; OPTN optineurin; ATXN2 ataxin 2; DAO D-amino acid oxidase; SPG11 spastic paraplegia 11; VCP valosin containing protein; SIGMAR1 sigma non-opioid intracellular receptor 1; TAF15 TATA-box binding protein associated factor 15; UBQLN2 ubiquilin-2; SQSTM1 sequestosome 1; PFN1 profilin-1; HNRNPA1 heterogeneous nuclear ribonucleoprotein A1; ERBB4 erb-2 receptor tyrosine kinase 4; MATR3 matrin 3; TUBA4A tubulin alpha-4a; TBK1 TANK-binding kinase 1

Mentions: Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disorder in adults. It is characterized by progressive death of upper and lower motor neurons. This degeneration leads to paralysis and to patient death within 2 to 5 years after disease onset. In the last ten years, a wide variety of gene mutations have been discovered for the familial form of the disease (fALS), leading to an impressive genetic heterogeneity. Expanded hexanucleotide repeats in C9orf72 account for nearly 35 % of familial cases, mutations in superoxide dismutase 1 (SOD1) for 20 %, mutations in TAR DNA-binding protein (TARDBP) encoding TDP-43 and fused in sarcoma (FUS) for 4 % each. Other genes like p62 (SQSTM1), Ubiliquin-2 (UBQLN2), TANK-binding kinase 1 (TBK1) and Optineurin (OPTN) account for less than 1 % each [1] (Fig. 1). Genetic heterogeneity and other unknown causes of the sporadic form of ALS (sALS) lead to a phenotypic variability which increases treatment complexity of the disease. Numerous pathological cellular mechanisms are identified in ALS and have been recently reviewed [2]. This includes oxidative stress, mitochondrial defect, axonal transport impairment, protein aggregation, excitotoxicity, endoplasmic reticulum stress, abnormal RNA processing and neuroinflammation with a role of non-neuronal cells (Fig. 1). These mechanisms will not be further discussed in this review.Fig. 1


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)

Timeline of gene discovery and pathogenic mechanisms in ALS. Schematic representation of years of discovery of most important genes implicated in ALS. Mutation in the superoxide dismutase 1 (SOD1) represent approximately 15 % of familial ALS cases (fALS), mutation in C9orf72 represent 35-40 % and both TAR-DNA-binding protein (TARDBP) and Fused in sarcoma (FUS) for 4 % each. Other genes represent less than 1 % each. Protein aggregation and gliosis are pathological hallmark of ALS and have been discovered before the beginning of the illustrated timeline. ER endoplasmic reticulum; NEFH neurofilament heavy; ALS2 alsin; DCTN1 dynactin; PRPH peripherin; SETX senataxin; VAPB vesicle-associated membrane protein-associated protein B; CHMP2B Charged multivesicular body protein 2B; ANG angiogenin; FIG4 phosphoinositide 5-phosphatase; OPTN optineurin; ATXN2 ataxin 2; DAO D-amino acid oxidase; SPG11 spastic paraplegia 11; VCP valosin containing protein; SIGMAR1 sigma non-opioid intracellular receptor 1; TAF15 TATA-box binding protein associated factor 15; UBQLN2 ubiquilin-2; SQSTM1 sequestosome 1; PFN1 profilin-1; HNRNPA1 heterogeneous nuclear ribonucleoprotein A1; ERBB4 erb-2 receptor tyrosine kinase 4; MATR3 matrin 3; TUBA4A tubulin alpha-4a; TBK1 TANK-binding kinase 1
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4940869&req=5

Fig1: Timeline of gene discovery and pathogenic mechanisms in ALS. Schematic representation of years of discovery of most important genes implicated in ALS. Mutation in the superoxide dismutase 1 (SOD1) represent approximately 15 % of familial ALS cases (fALS), mutation in C9orf72 represent 35-40 % and both TAR-DNA-binding protein (TARDBP) and Fused in sarcoma (FUS) for 4 % each. Other genes represent less than 1 % each. Protein aggregation and gliosis are pathological hallmark of ALS and have been discovered before the beginning of the illustrated timeline. ER endoplasmic reticulum; NEFH neurofilament heavy; ALS2 alsin; DCTN1 dynactin; PRPH peripherin; SETX senataxin; VAPB vesicle-associated membrane protein-associated protein B; CHMP2B Charged multivesicular body protein 2B; ANG angiogenin; FIG4 phosphoinositide 5-phosphatase; OPTN optineurin; ATXN2 ataxin 2; DAO D-amino acid oxidase; SPG11 spastic paraplegia 11; VCP valosin containing protein; SIGMAR1 sigma non-opioid intracellular receptor 1; TAF15 TATA-box binding protein associated factor 15; UBQLN2 ubiquilin-2; SQSTM1 sequestosome 1; PFN1 profilin-1; HNRNPA1 heterogeneous nuclear ribonucleoprotein A1; ERBB4 erb-2 receptor tyrosine kinase 4; MATR3 matrin 3; TUBA4A tubulin alpha-4a; TBK1 TANK-binding kinase 1
Mentions: Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disorder in adults. It is characterized by progressive death of upper and lower motor neurons. This degeneration leads to paralysis and to patient death within 2 to 5 years after disease onset. In the last ten years, a wide variety of gene mutations have been discovered for the familial form of the disease (fALS), leading to an impressive genetic heterogeneity. Expanded hexanucleotide repeats in C9orf72 account for nearly 35 % of familial cases, mutations in superoxide dismutase 1 (SOD1) for 20 %, mutations in TAR DNA-binding protein (TARDBP) encoding TDP-43 and fused in sarcoma (FUS) for 4 % each. Other genes like p62 (SQSTM1), Ubiliquin-2 (UBQLN2), TANK-binding kinase 1 (TBK1) and Optineurin (OPTN) account for less than 1 % each [1] (Fig. 1). Genetic heterogeneity and other unknown causes of the sporadic form of ALS (sALS) lead to a phenotypic variability which increases treatment complexity of the disease. Numerous pathological cellular mechanisms are identified in ALS and have been recently reviewed [2]. This includes oxidative stress, mitochondrial defect, axonal transport impairment, protein aggregation, excitotoxicity, endoplasmic reticulum stress, abnormal RNA processing and neuroinflammation with a role of non-neuronal cells (Fig. 1). These mechanisms will not be further discussed in this review.Fig. 1

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