Amyotrophic Lateral Sclerosis: Perspectives from Genetics · Amyotrophic Lateral Sclerosis:...

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Amyotrophic Lateral Sclerosis: Perspectives from Genetics Robert H. Brown, Jr., D.Phil., M.D. University of Massachusetts Medical Center for Shirley H. Wray Collection NOVEL Library August 7, 2008 Boston, MA Department of Neurology Massachusetts General Hospital Harvard Medical School

Transcript of Amyotrophic Lateral Sclerosis: Perspectives from Genetics · Amyotrophic Lateral Sclerosis:...

Amyotrophic Lateral Sclerosis: Perspectives from Genetics

Robert H. Brown, Jr., D.Phil., M.D.

University of Massachusetts Medical Center

for Shirley H. Wray Collection

NOVEL Library

August 7, 2008 Boston, MA

Department of Neurology

Massachusetts General Hospital Harvard Medical School

Mutations Mendelian and Complex Genetics Mechanisms Recent lessons in pathophysiology Medicines Therapeutic advances

Presenter
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ALS is a devastating orphan disease

Incidence Total 1-2/100,000 3,000-6,000 US 70,000 World Prevalence 5/100,000 ~20,000 US 500,000 World

Mean age of onset = 55 years

….. uniformly fatal, in 4-5 years.

The hallmark of ALS is muscle denervation and atrophy due to loss of spinal motor neurons; this begins focally.

Degeneration of brain motor neurons causes spasticity.

Ross 1881

Cytoskeletal pathology and ubiquitinated protein aggregates are seen in motor neurons.

axonal spheroid

ubquitinated proteins

Ubiquitinated proteins in most ALS motor neurons include TDP-43.

Neumann M, Trojanowski J, Lee V et al. , Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130-133, 2006.

nuclear protein transcription repressor part of splicing apparatus in early ALS and FTD

cleaved hyperphosphorylated ubiquitinated

There is neuroinflamation in ALS spinal cord.

ALS Control

McGeer PL, McGeer PG. Muscle and Nerve 26: 459–470, 2002

Activated microglia in anterior gray matter of ALS spinal cord.

The development of ALS probably reflects an interplay: environment, genetic factors, and chance, aging.

The development of ALS probably reflects an interplay: environment, genetic factors, and chance, aging.

Factor Odds Ratio Toxins Agricultural Toxins -- herbicides 3.0 -- fertilizers 2.3 Metals -- lead exposure 1.6 Respiratory -- smoking 3.3 Infectious Agents -- retroviruses -- Lyme -- other Infectious Toxins Diet -- high fat 3.8 -- high glutamate 3.2 -- high fiber 0.3

The development of ALS probably reflects an interplay: environment, genetic factors, and chance, aging.

10% of ALS: autosomal dominant

Amyotrophic Lateral Sclerosis: 13 Mendelian loci, 7 genes

ALS1 AD 21q SOD1ALS2 AR 2q alsinALS3 AD 18q ?ALS4 AD 9q senataxinALS5 AD 15q ?ALS6 AD 16q ?ALS7 AD 20p ?ALS8 AD 20q VAPBALS AD 2p dynactinALS AD 1p TDP-43ALS AR 19p NTE

ALS-FTD AD 9q ?ALS-X AD X cen ?

Amyotrophic Lateral Sclerosis: 13 Mendelian loci, 7 genes

5 have ALS or ALS-like phenotype

*

* *

ALS1 AD 21q SOD1ALS2 AR 2q alsinALS3 AD 18q ?ALS4 AD 9q senataxinALS5 AD 15q ?ALS6 AD 16q ?ALS7 AD 20p ?ALS8 AD 20q VAPBALS AD 2p dynactinALS AD 1p TDP-43ALS AR 19p NTE

ALS-FTD AD 9q ?ALS-X AD X cen ?

*

*

Mutations Mendelian Genetics - FALS Mechanisms Recent lessons in pathophysiology Medicines Therapeutic advances

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William Osler 1890 First description of familial ALS

1849-1919

10% of ALS cases are inherited as a dominant, highly penetrant (>90%) trait.

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25% of familial ALS (3% of all ALS) arises from mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1).

135 mutations (124 missense, 11 truncation)

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SOD1A4V cases are common in North America but rare in Europe;

extremely rapidly progressive MND.

A4V Farr Family

In northern Sweden, SOD1D90A/+ are asymptomatic; SODD90A/D90A slowly progressive MND.

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A4V

The A4V variant of SOD1 arose in Asia and was carried across the Bering Strait about 10,000 years ago.

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Amyotrophic Lateral Sclerosis: Mendelian loci

ALS1 AD 21q SOD1ALS2 AR 2q alsinALS3 AD 18q ?ALS4 AD 9q senataxinALS5 AD 15q ?ALS6 AD 16q ?ALS7 AD 20p ?ALS8 AD 20q VAPBALS AD 2p dynactinALS AD 1p TDP-43ALS AR 19p NTE

ALS-FTD AD 9q ?ALS-X AD X cen ?

Tunisian family Kuwaiti family

• corticospinal, corticobulbar signs • lower motor neuron signs

• exclusively corticospinal, corticobulbar signs • no lower motor neuron findings

Ben Hamida, M., et al., Brain 113, 347-363 (1990).

Lerman-Sagie, T, Filiano, J., Smith, D.W. & Korson, M. J. Child Neurol. 11, 54-57 (1996).

ALSIN deficiency in juvenile ALS causes defective microtubule assembly, motility and trafficking of cellular

constituents.

Rho-GEF

Nuclear trafficking,

spindle formaion, microtubule assembly

Signaling cell growth, motility

Protein, vesicle,

endocytitc trafficking

Ran-GEF Rab5-GEF

• 184 kd • Prominently expressed in large neurons • Implicated in vesicle trafficking

Yang, Y., et al , Nat Genet, 2001. 29(2): p. 160-5. Hadano, S., et al., Nat Genet, 2001. 29(2): p. 166-73.

Amyotrophic Lateral Sclerosis: Mendelian loci

ALS1 AD 21q SOD1ALS2 AR 2q alsinALS3 AD 18q ?ALS4 AD 9q senataxinALS5 AD 15q ?ALS6 AD 16q ?ALS7 AD 20p ?ALS8 AD 20q VAPBALS AD 2p dynactinALS AD 1p TDP-43ALS AR 19p NTE

ALS-FTD AD 9q ?ALS-X AD X cen ?

Dynactin subunit mutations are implicated in MND.

• Onset average 34 (23-44) • Dominant inheritance • Predominantly lower MNs • Early stridor and shortness of breath

– vocal fold paralysis • Weakness in hands > arms and legs • Thenar weakness early • Steppage gait late • Chronic reinnervation by EMG

Puls I, Oh S, Sumner CJ, Wallace KE, Floeter MK, Mann EA, Kennedy WR, Wendelschafer-Crabb G, Vortmeyer A, Powers R, Finnegan K, Holzbaur ELF, Fischbeck KH, Ludlow CL. Distal Spinal and Bulbar Muscular Atrophy

Caused by Dynactin Mutation. Ann Neurol 2005;57:687–694

Dynactin subunit mutations are implicated in MND.

Puls I, et al. Ann Neurol 2005;57:687–694

Release

KINESIN

DYNEIN (dynactin)

Anterograde transport

Retrograde transport

Microtubules

Anterograde cargo

Neurotrophic factors

Mitochondrion

Retrograde cargo

Dynein-Dynactin complex (retrograde motor) Kinesin (anterograde motor)

Golgi - ER

Synthesis and trafficking of vesicles and proteins

Nucleus

Uptake

Neurofilaments

Amyotrophic Lateral Sclerosis: Mendelian loci

ALS1 AD 21q SOD1ALS2 AR 2q alsinALS3 AD 18q ?ALS4 AD 9q senataxinALS5 AD 15q ?ALS6 AD 16q ?ALS7 AD 20p ?ALS8 AD 20q VAPBALS AD 2p dynactinALS AD 1p TDP-43ALS AR 19p NTE

ALS-FTD AD 9q ?ALS-X AD X cen ?

AJHG 82:780, 2008

- Juvenile onset - Corticospinal and lower motor neurons involved - No known exposure to organophosphates

Mendelian Genes other loci: chr 9p, 16p Complex Genetics Other considerations

Mendelian Genes unusual phenotypes Complex Genetics Other considerations

Novel Motor Neuron Disease Phenotype Madras Motor Neuron Disease:

Juvenile onset of motor weakness and deafness Rapidly progressive, severely disabling

Drs. Gourie-Devi, Nalini, Nithin NIMHANS, Bangalore

Dr. C. Thangaraj CCMB, Hyderabad

Overview: More than 60 gene defects

cause human motor neuron diseases (ALS, HSP, SMA, X-SBMA, PN)

These gene defects implicate common elements

in the pathogenesis of these diseases:

Axonal motors and filaments (7) vesicle trafficking (4) DNA/RNA metabolism (6) Cell signaling (5) Heat shock proteins (3)

Mutations Complex Genetics - SALS (1) Candidate genes in SALS Mechanisms Recent lessons in pathophysiology Medicines Therapeutic advances

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Candidate genes in sporadic ALS* • VEGF

• Angiogenin

• Survival Motor Neuron

• Neurofilaments

• 35 other MN disease genes

* implicated in some but not all populations studied

Angiogenin

• 14 kda • Multifunctional

– Promotes angiogenesis – Ribonuclease – Permissive for VEGF

• 7 variants implicated in SALS. – Scotland, Ireland – Not US, UK

Greenway MJ, Hardiman O et al. Nat Genet 2006:38:411-413.

• Paraoxonases PON1, PON2, and PON3 • Gene cluster, chr 7

• Hydrolases • PON1 and PON3

– expressed in the liver – associated with HDL

• PON2

– intracellular, also associated with a plasma membrane – ubiquitous

• Functions: – antioxidative: attenuate lipid peroxidation by LDL anti-atherogenic – cytoprotective: inactivate wide range of toxins

Paraoxonases (PON) may be risk factors for SALS

Properties of PON1

• 41 kd - monomer • conserved in evolution • central hydrophobic channel • 6 bladed propeller

c

Harel et al. Nat Str Biol 11(5):412, 2004

• Ca in active site • 3 helices closed channel • Insert into HDL particle membranes • Highly polymorphic • Multiple substrates

Slowik A, Figlewicz DA et al. Paraoxonase gene polymorphisms and sporadic ALS. Neurology, epub July, 2006 PON1

Saeed M, Siddique T et al. Paraoxonase cluster polymorphisms are associated with sporadic ALS. Neurology, epub July, 2006. PON2 Morahan JM, Yu B, Trent RM, Pamphlett R. A gene environment study of the paroxonase 1 gene and pesticides in amyotrophic lateral sclerosis. Neurotoxicology, 2006. PON1.

Cronin S, Greenway MJ, Prehn JHM, Hardiman O. Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2007;78:984–986. PON1

Paraoxonases (PON) may be risk factors for SALS

HYPOTHESIS – diminished toxin degradation or anti-oxidant capacity predisposes to ALS.

Mutations Complex Genetics (2) SNP-based genome analyses in SALS Mechanisms Recent lessons in pathophysiology Medicines Therapeutic advances

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Summary Whole Genome Analyses in ALS

2007-2008

• ITPR2 – highly expressed in motor neurons • Controls release of calcium from ER – calibrating intracellular

calcium levels in motor neurons • Release is mediated by inositol tri-phosphate • Excessive Ca2+ is potentially toxic via multiple mechanisms

Mutations Mendelian and Complex Genetics Mechanisms Recent lessons in pathophysiology Medicines Therapeutic advances

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Over-expression of mutant SOD1 generates animal models of ALS.

G93A mouse (Day Lab)

H46R rat (Day Lab)

A4V fly (Mel Feaney, HMS)

ALS worm (Rick Morimoto)

ALS zebrafish

Mouse experiments reveal that mutant SOD1 protein is cytotoxic.

Mouse SOD1 Human SOD1 (transgene) Mouse Type Phenotype

SOD1 KO

Normal

Tg–WT SOD1 Normal

Mouse level WT human level Mutant human level

Naive

Normal

ALS Tg–Mut SOD1

3% of ALS arises from mutations in the gene encoding cytosolic Cu/Zn superoxide dismutase (SOD1).

SOD1 catalyzes the conversion of superoxide anion to oxygen and hydrogen peroxide.

Transgenic expression of mutant SOD1 apoenzyme, devoid of Cu, mouse ALS.

G93A mouse (Day Lab)

X X

X X X

Hypothesis: the critical factor in SOD1mutant ALS is conformational instability of this abundant protein.

SOD1 dimer

Unstable monomer

Pore-like proto-aggregate Large aggregate

Mutant

Wildtype

Toxicity

Instability of the mutant SOD1 protein contributes to its toxicity

Excessive bursting Abnormal axonal transport

Early axonal

retraction

Early events in ALS are intrinsic to the motor neurons.

Binds mSOD1 Decreased ATP, Ca++

apoptosis

Squid Loligo pealii Drs. Scott Brady, Gerardo Morfini, University of Illinois, Wood Hole Hannah Brown, Harvard Medical School, Woods Hole

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• isolated axon

• not influenced by - cell body - gene transcription

• direct impact of SOD1 on transport motor apparatus

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Rat

e of

tran

spor

t

Cell body NM Junction

Anterograde

Retrograde

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Normal SOD1 has no effect on transport.

Anterograde

Retrograde

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SOD1 mutants slow anterograde transport.

SOD1 mutants impair the function of axonal kinesin, probably by altering phosphorylation.

Retrograde

Anterograde

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Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien J-P. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic

lateral sclerosis. Nat Neurosci 9:108-118, 2006.

CgA CgA

Microglia Astrocytes

Inactive

Active

Mutant SOD1 binds chromogranin and is secreted.

Late events in ALS involve non-neuronal cells, with diverse influences on motor neurons.

Activated astrocyte

AstrocytesmutSOD1 adversely affect motor neurons in vitro.

Co-culture of stem-cell derived MNs and astrocytes

Surv

ivng

Mot

or N

euro

ns

WT MNs + WT Glia

+ Glia mut SOD1

DiGeorgio, Carrasco, Siao, Maniatis, Eggan Nature Neuroscience 19(5):608-614, 2007

Activated microglia in ALS can be both toxic and beneficial in vivo

Reduction of oxidative bursting by microglia (NADPH / Nox2 knock-out)

enhances survival in SOD1G93A mice.

Marden JJ, Harraz MM, Williams AJ, Nelson K, Luo M, Paulsen H, Englehardt JF. Redox modifier genes in amyotrophic lateral sclerosis. J Clin Inv 119(10):2913, 2007

Does neuroinflamation alter disease course?

Time (Months)

Aspirin use __ __ __ No aspirin use _______

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60

Aspirin use __ __ __ No aspirin use _______

Time (Months)

Surv

ival

Fr

actio

n

Merit Cudkowicz (MGH)

Retrospective analysis of 4 studies, n=596: topiramate placebo, celebrex, creatine, MGH longitudinal 2/15 meds affected survival: ASA, NSAIDs

Survival

10 months

Does this relate to sporadic ALS?

Does this relate to sporadic ALS?

WT SOD1 is neurotoxic when oxidized.

Ezzi SA, Urushitani M, Julien J-P. Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. epub 2007

M

otor

Neu

ron

Surv

ival

Protein

SOD1 G93A

WT SOD1 OXID

WT SOD1

Motor Neurons

TNFα

Sec

retio

n

SOD

1 G

93A

WT

SOD

1

Con

trol

WT

SOD

1 O

XID

Microglia

Mab C4F6 recognizes a toxic form of mutant SOD1 protein.

MAB C4F6

Mutant SOD1

Urushitani M, Ezzi SA, Julien J-P. PNAS 104(7): 2495-2500, 2007

G93A G37R G85R

Mab C4F6 reacts with a sub-fraction of WT-SOD1 in SALS spinal cords.

Julien J-P personnal communication

Spinal cord CSF G37R

ControlSALS SALS

SALS

Sporadic ALS

Spinal cord

CSF

Hypothesis: Some cases of sporadic ALS are mediated by modified WT

SOD1, with toxicity similar to that of mutant SOD1.

MAB C4F6

Mutant SOD1

WT-SOD1 Post-translational

modifications

Mutations Mendelian and Complex Genetics Mechanisms Recent lessons in pathophysiology Medicines Therapeutic advances

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Only one drug is FDA approved for ALS (Riluzole) but...

….the ALS pipeline has many drugs in trials

• Minocycline • IGF-1 (#3) • Ceftriaxone • Sodium Phenylbutrate • Coenzyme Q10 • Thalidomide • Ritonavir/hydroxyurea • Valproic acid • Copaxone • Memantine • Celebrex/Creatine vs

Minocycline/Creatine

• Arimoclomol (phase IIB) • Talampanal • Trophos • R+ Pramipexole

Current Planned

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• Stem Cells • Drug discovery • Gene therapy • Protein delivery • Allele inactivation • Protein inactivation

Understanding molecular pathology in ALS has aided therapy development

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• Stem Cells • Drug discovery • Gene therapy • Protein delivery • Allele inactivation • Protein inactivation

Understanding molecular pathology in ALS has aided therapy development

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Microwell screening can be done with high throughput: >200,000 drugs tested/day

400 cases $10 M / 3 years

40 mice $50 K / 6 mo’s

2 wells $5 / 24 hr

2 x 106 less expensive

103 faster

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Instability of the mutant SOD1 protein contributes to its toxicity.

Stabilization of the dimer may be beneficial.

SOD1 dimer

Unstable monomer Pore-like proto-aggregate Large non-toxic aggregate

Mutant

Wildtype

Toxicity

1.5 million compounds

3000 molecules are predicted to stabilize SOD1

Parallel processing on Beowulf cluster speed up computation.

Computational Docking: A fast and effective way to screen big libraries of compounds

S. Ray

1.5 million compounds

3000 molecules predicted to bind SOD1

Parallel processing on Beowulf cluster speed up computation.

Computational Docking: A fast and effective way to screen big libraries of compounds

S. Ray

SO

N

NHN

O

(1)

NH

O NH

O

NH

Cl

(2)

NH

NHN

O

S

Cl

O

(3)

NH

NHN

S

S

CH3

O

(4)

NH

NHN

O

S

F

O

(7)

NH2

CH3

NH2

CH3(6)

NOH

Br

F(5)

NHNH

NH2O

F

(8)

OH

NH

NH2

O

(9) NH2

NH

N

OH

O

(10)

NH

N NH

NH2O

(12)

NH

NH2

O

OH(13)

F

OH

O

OH

OH

CH3OH

O

CH3

(14)

N

N

NNH

2

N

O

O

P

OH

OO

H

OH

OH

(15)

S

N

NH2

O

(11)

Multiple molecules identified by cyber-pharmacology do stabilize SOD1.

Ray SS, Nowak RJ, Brown, RH Jr., Lansbury PT. Inhibition of aggregation of familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutants by drug-like structural stabilizers PNAS,102(10),3639-3644, 2005

• Stem Cells • Drug discovery • Gene therapy • Protein delivery • Allele inactivation • Protein inactivation

Understanding molecular pathology in ALS has aided therapy development

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Viral vectors may allow delivery of genes to the nervous system – e.g. by retrograde transport from muscles.

Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science. 301:839-842, 2003.

AAV2 – IGF1

AAV2-IGF1 gene therapy potently increases ALS survival.

AAV-IGF1 delivered- 60 days old

IGF-1 GDNF

GFP

Survival

AAV2-IGF1 gene therapy potently increases ALS survival.

AAV-IGF1 delivered- 60 days old

IGF-1 GDNF

GFP

Survival

40 days

• Stem Cells • Drug discovery • Gene therapy • Protein delivery • Allele inactivation • Protein inactivation

Understanding molecular pathology in ALS has aided therapy development

Presenter
Presentation Notes
Text slide – all text, charts, graphs, photos, etc.

• Stem Cells • Drug discovery • Gene therapy • Protein delivery • Allele inactivation • Protein inactivation

Understanding molecular pathology in ALS has aided therapy development

Presenter
Presentation Notes
Text slide – all text, charts, graphs, photos, etc.

Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model.

Ralph GS, Azzouz M et al.. Nat Medicine 11(4):424-433, 2005

Rabies-G-pseudotyped EIAV lentivirus Many muscle injections at age 7 days (face, tongue, diaphragm, intercostal muscles, hindlimb) At end-stage: more MN persisted in treated than in untreated mice

Ralph GS, Radcliffe PA, Day DM, Carthy JM, Leroux MA, Lee DCP, Wong L-F, Bilsland LG, Greensmith L, Kingsman SM, Mitrophanous KA, Mazarakis ND, Azzouz M. Silencing mutant SOD1

using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 11(4):424-433, 2005.

Ralph GS, Radcliffe PA, Day DM, Carthy JM, Leroux MA, Lee DCP, Wong L-F, Bilsland LG, Greensmith L, Kingsman SM, Mitrophanous KA, Mazarakis ND, Azzouz M. Silencing mutant SOD1

using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 11(4):424-433, 2005.

100 days

Trials of allele inactivation therapy for SOD1-mediated ALS are planned (Isis)

Intraventricular infusion of anti-SOD1 anti-sense oligonucleotides prolongs survival in transgenic SOD1G93A rats.

Smith RA, Mller T, Bennett CF, Cleveland DW et al. J. Clin. Inv. 116(8): 2290-2296, 2006.

∆ 2 weeks

• Stem Cells • Drug discovery • Gene therapy • Protein delivery • Allele inactivation • Protein inactivation

Understanding molecular pathology in ALS has aided therapy development

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Will vaccination therapy inactivate toxic proteins in ALS?

Vaccination with SOD1 prolongs survival in ALS mice and reduces titer of toxic form of SOD1.

C4F

6 (+

) mut

ant S

OD

1

Sur

viva

l Fra

ctio

n

∆ 25 days

Urushitani M, Ezzi SA, Julien J-P. Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. PNAS 104(7): 2495-2500, 2007

Conclusions

• Four gene defects cause familial ALS; PON gene variants may be robustly associated with SALS.

• In SOD1mutant ALS, pathological processes

– multi-factorial and begin early. – biphasic

• initially intrinsic to motor neurons • then involve non-neural cells (neuroinflamation).

• WT SOD1 may be implicated in some cases of SALS.

• These molecular insights are yielding new therapeutic strategies in ALS.

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Thank You!

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