Amyotrophic lateral Amyotrophic lateral sclerosis (ALS)sclerosis (ALS)

What is amyotrophic What is amyotrophic lateral sclerosis?lateral sclerosis?

It is a progressive It is a progressive neurological disease neurological disease that affects the control that affects the control of muscle movement of muscle movement due to its damaging due to its damaging affects on motor affects on motor neurons in the spinal neurons in the spinal cord and the brain cord and the brain

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Significance of the Significance of the Name of this DiseaseName of this Disease

A-myo-trophic comes from GreekA-myo-trophic comes from Greek ““A” = no/negativeA” = no/negative ““myo” = musclemyo” = muscle ““trophic” = nourishment trophic” = nourishment ““No Muscle Nourishment”No Muscle Nourishment”

Lateral = defines location of the nerve cells that Lateral = defines location of the nerve cells that signal and control the musclessignal and control the muscles

Sclerosis = scarring and hardening in the Sclerosis = scarring and hardening in the degenerating regiondegenerating region

From www.als.orgFrom www.als.org

Other common names Other common names for this disease:for this disease:

Motor neuron disease Motor neuron disease Charcot’s diseaseCharcot’s disease

Lou Gehrig’s diseaseLou Gehrig’s disease

Picture from the Neuromuscular website

Who was Lou Gehrig?Who was Lou Gehrig?

Lou Gehrig Lou Gehrig was a was a baseball baseball player for player for the New York the New York Yankees in Yankees in the late the late 1920s and 1920s and 1930s1930s

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What genes are What genes are related to ALS?related to ALS?

Copper/zinc Superoxide Copper/zinc Superoxide dismutase 1 (SOD1)dismutase 1 (SOD1)

Heavy neurofilament subunit Heavy neurofilament subunit (NEFH)(NEFH)

Peripherin (PRPH)Peripherin (PRPH) Dynactin (DCTN1)Dynactin (DCTN1)

This disease affects This disease affects SOD1 gene on SOD1 gene on

chromosome 21chromosome 21

Mutations occurs at the SOD1 located on the long arm of Chromosome 21

Cu/Zn Superoxide Cu/Zn Superoxide dismutase 1 genedismutase 1 gene

Codes for the protein Cu/Zn Codes for the protein Cu/Zn Superoxide dismutase 1Superoxide dismutase 1

Contains 5 exons and 4 intronsContains 5 exons and 4 introns mRNA is 981 base pairs longmRNA is 981 base pairs long

Structure of SOD1 Structure of SOD1 ProteinProtein

SOD1 proteinSOD1 protein

Removes dangerous superoxide radicals by converting Removes dangerous superoxide radicals by converting them to non-harmful substancesthem to non-harmful substances

O2 O2 ̄ + O2 ̄ + 2H+ ̄ + O2 ̄ + 2H+ → O2 + H2O2→ O2 + H2O2

Protein contains 154 amino acidsProtein contains 154 amino acids

Has one domain, SOD_CuHas one domain, SOD_Cu

Mutations in SOD1 Mutations in SOD1 proteinprotein Several different mutations in this Several different mutations in this

enzyme may all result in ALS, enzyme may all result in ALS, making the exact molecular making the exact molecular cause of the disease difficult to cause of the disease difficult to ascertainascertain

Mutations in SOD1 Mutations in SOD1 protein continued . . . protein continued . . .

Some mutations in SOD1 Some mutations in SOD1 associated with ALS:associated with ALS:– R4VR4V– G93AG93A– G37RG37R– G16SG16S

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Nature and Nature and Characteristics of ALSCharacteristics of ALS

Forms:Forms:– Two types of ALS:Two types of ALS:

Sporadic – no family history Sporadic – no family history Familial – family history/backgroundFamilial – family history/background

– 90% of the known cases are 90% of the known cases are sporadicsporadic

ALS continued . . . ALS continued . . .

Types of Familial Types of Familial – Autosomal dominant Autosomal dominant – Autosomal recessiveAutosomal recessive– X-linked dominant X-linked dominant

Sporadic Sporadic

Who Gets ALS?Who Gets ALS?

““According to the ALS CARE According to the ALS CARE Database, 60% of the people with Database, 60% of the people with ALS in the database are men and ALS in the database are men and 93% of patients in the database 93% of patients in the database are caucasian.”are caucasian.”

Normally occurs in people Normally occurs in people between 40 to 70 years of agebetween 40 to 70 years of age– Also can occur in people in their 20’s Also can occur in people in their 20’s

and 30’s and 30’s From The ALS Association

Cause of ALSCause of ALS

Due to a mutation in SOD1, the Due to a mutation in SOD1, the superoxide radicals are not superoxide radicals are not neutralizedneutralized

The radicals attack the motor The radicals attack the motor neurons and degrade themneurons and degrade them

Muscles are not able to be Muscles are not able to be stimulatedstimulated

Symptoms of ALSSymptoms of ALS

First signs and First signs and symptoms (frequently symptoms (frequently overlooked)overlooked)– Twitching and cramping Twitching and cramping

of muscles (especially in of muscles (especially in hands and feet)hands and feet)

– StiffnessStiffness– Weakness (especially in Weakness (especially in

hands, arms and legs)hands, arms and legs)– Slurred speechSlurred speech

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Symptoms Symptoms continued . . . continued . . .

Later signs and Later signs and symptoms:symptoms:– Difficulty chewing and Difficulty chewing and

swallowingswallowing– Shortness of breathShortness of breath– Muscle weakness due Muscle weakness due

to wasting away of to wasting away of muscles muscles

Causes muscles to Causes muscles to become smallerbecome smaller

– Respiratory failure Respiratory failure – ParalysisParalysis

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This picture from This picture from the the Neuromuscular Neuromuscular website shows website shows the wasting away the wasting away of a person’s of a person’s hands and armshands and arms

Symptoms, or patterns of symptoms, are not Symptoms, or patterns of symptoms, are not the same for each ALS individualthe same for each ALS individual

However, progressive muscle weakness and However, progressive muscle weakness and paralysis are universally experiencedparalysis are universally experienced

Since ALS attacks only motor neurons, the Since ALS attacks only motor neurons, the sense of sight, touch, hearing, taste, and sense of sight, touch, hearing, taste, and smell are not affectedsmell are not affected

Patients usually only live 3 to 5 years after Patients usually only live 3 to 5 years after they are diagnosedthey are diagnosed

There are some cases; however, where There are some cases; however, where individuals have lived 10 or more yearsindividuals have lived 10 or more years

Diagnosing ALSDiagnosing ALS

5,600 people in the US 5,600 people in the US are diagnosed with ALS are diagnosed with ALS each yeareach year

ALS is a very difficult ALS is a very difficult disease to diagnosedisease to diagnose

Blood tests, Urine tests, Blood tests, Urine tests, Spinal taps, x-rays, Spinal taps, x-rays, muscle or nerve muscle or nerve biopsies, or a biopsies, or a neurological neurological examinations are examinations are administeredadministered

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Medication for ALSMedication for ALS

Rilutek (brand name) / riluzole Rilutek (brand name) / riluzole (generic) – slows progression of (generic) – slows progression of ALSALS– It is the only prescription drug for It is the only prescription drug for

ALSALS– Approved in December 1995 Approved in December 1995

From the MDA PublicationsFrom the MDA PublicationsPicture from healthlit.org

HypothesisHypothesis

The mechanisms The mechanisms that cause that cause mutations in mutations in SOD1 that lead SOD1 that lead to ALS are to ALS are unknownunknown

Hypothesis #1 Hypothesis #1

An increase or a decrease in the An increase or a decrease in the activity of SOD1 may cause ALSactivity of SOD1 may cause ALS– We theorized that a decrease, rather We theorized that a decrease, rather

than an increase, may be the cause of than an increase, may be the cause of ALS.ALS.

– Theory: decrease = produces more Theory: decrease = produces more harmful free radicalsharmful free radicals

– We searched NCBI in support for both an We searched NCBI in support for both an increase and a decrease in SOD1 activity increase and a decrease in SOD1 activity

Support from NCBISupport from NCBI

One study conducted by One study conducted by Rosen found that Rosen found that increased levels of increased levels of expression of SOD1 in expression of SOD1 in mice would produce mice would produce excessive levels of excessive levels of hydrogen peroxidehydrogen peroxide

From OMIM

Picture from The ALS Society of Canada

Support continued . . .Support continued . . .

According to Kunst over-According to Kunst over-expression of normal SOD1 expression of normal SOD1 accelerates disease onset and accelerates disease onset and progression progression – However, a decrease or increase in However, a decrease or increase in

SOD1 activity is not sufficient to SOD1 activity is not sufficient to cause ALS in micecause ALS in mice

From PubMed

Hypothesis #2Hypothesis #2

SOD1 may lose its SOD1 may lose its ability to bind zinc ability to bind zinc (Zn), Copper (Cu), or (Zn), Copper (Cu), or both both

– This may cause SOD1 This may cause SOD1 to lose its ability to to lose its ability to process free radicals process free radicals

From MDA Publications

Support from NCBISupport from NCBI

Zinc and Copper = normalZinc and Copper = normal Zinc removed = toxicZinc removed = toxic Zinc and Copper removed = non-toxicZinc and Copper removed = non-toxic Copper removed = not studied yetCopper removed = not studied yet

Zinc that is bound to SOD1 may Zinc that is bound to SOD1 may stabilize the proteinstabilize the protein

From PubMed

Support continued . . . Support continued . . .

Zinc-deficient SOD1 produces Zinc-deficient SOD1 produces more free radicals than it more free radicals than it destroysdestroys

SOD1 mutant can not bind zinc as SOD1 mutant can not bind zinc as strongly as normal SOD1strongly as normal SOD1

CreditsCredits

NCBINCBI ALS OrganizationALS Organization National Institute of Aging The ALS Association The ALS Society of Canada MDA PublicationsMDA Publications Memory & Aging CenterMemory & Aging Center Neuromuscular websiteNeuromuscular website lougehrig.comlougehrig.com coolrunning.comcoolrunning.com healthlit.orghealthlit.org