Amyotrophic Lateral Sclerosis (ALS) - aka Lou Gehrig's Disease presentation by Nat Royer

Amyotrophic Lateral Sclerosis (ALS)‫‏‬
               aka
       Lou Gehrig's Disease

             presentation by
                Nat Royer

A (negative) myo (muscle) trophic (nourishment)‫‏‬
         Lateral (location in spinal cord)‫‏‬
             Sclerosis (hardening)‫‏‬

       http://www.alsa.org/images/cms/Research/Topics/disease_process.jpg

Epidemiology

   An estimated 30,000 Americans have ALS
   Most are between the ages of 40-70
   50% live more than 3 years, 10% live 10+
   Two main types of ALS
    −   90-95% of cases are sporadic ALS (SALS)‫‏‬
    −   5-10% have familial ALS (FALS)‫‏‬
    −   Guamanian

Notable People with ALS

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n/Lou_Gehrig_files/image001.jpg   appyscience/Stephen_Hawking.jp     uppet/images/7/78/Writer.jonstone.jp
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Lou Gehrig                         Stephen                            Jon Stone
                                   Hawkings

Signs & Symptoms
   Early symptoms: muscle weakness,
    tripping, slurred speech, muscle
    twitches
   Defective upper motor neurons:
    −   Stiff muscles and exaggerated
        reflexes
   Defective lower motor neurons:
    −   Muscle weakness, cramps, and
        twitches
   Eventual trouble swallowing,
    breathing, and standing, but usually
    retain all cognitive ability

Familial ALS

   10 year later age of onset
    than SALS
   Rarely exhibits typical
    dominant or recessive
    inheritance
   A few examples of
    complete penetrance in
    families have been
    studied to identify mutated
    genes

SOD1 in FALS

   In 1993 researchers discovered SOD1
    mutations in patients showing autosomal-
    dominant FALS
   Seen in 20% of FALS patients
   Over 100 different mutations in SOD1 have
    been shown to lead to ALS
   mSOD1 is often polyubiquitinated and forms
    aggregates

SOD1 in FALS

What makes mSOD1 neurotoxic?

   mSOD1 seems to cause ALS without affecting
    enzymatic activity
   May increase the unfolded states of SOD1 and
    lead to protein aggregates
   Could cause malfunction of proteasomal
    systems
   Might interact with dynein and interfere with
    retrograde axonal transport

mSOD1 and ER stress
   Suppression of
    protein translation
   Induction of ER
    chaperones
   Degradation of
    misfolded proteins via
    the ubiquitin-
    proteasome pathway
   Induction of
    apoptosis

Glial cell damage can contribute to ALS

   Jean-Pierre Julien found that astrocytes with
    SOD1 mutation can exacerbate neuronal death
   Removing mSOD1 from non-neuronal cells
    slows the progression of the disease
   Nagai et al. showed that this destructive
    relationship is specific between astrocytes and
    motor neurons
   The toxic factors released by astrocytes are still
    undetermined

Glial cell damage can contribute to ALS

Glutamate excitotoxicity and ALS

   Spreux-Varoquaux et al. found that 40% of 400
    patients with sporadic ALS had increased
    glutamate levels in cerebrospinal fluid
   Astrocytic glutamate transporter EAAT2 is
    responsible for clearance of synaptic glutamate
   Mutations in SOD1 have been shown to
    severely reduce levels of spinal EAAT2
   Repetitive firing leads to neuronal death

Glutamate excitotoxicity and ALS

Neurofilaments and ALS
   Many ALS patients display accumulation of
    neurofilaments in cell body and proximal axons
   Studies have shown that increasing
    neurofilaments in perikarya and decreasing
    them in axons is protective against ALS
   Perikarya accumulation could serve as a buffer
    against excessive Ca2+ levels and
    hyperphosphorylation of neuronal substrates
   Axonal accumulation interferes with axonal
    transport

Other possible causes of ALS

   Chronic activation of caspases causing
    apoptosis
   Deletion of hypoxia-response element in the
    VEGF gene
   Autoimmune response against motor neurons
   What can we do for therapies?

Treatments – NAD synthesis
   The majority of ALS cases have
    an unknown cause, so the goal
    is to treat neuron damage
   Jeffery Milbrandt at WashU
    demonstrated that mice with
    increased ability to synthesize
    NAD had slowed axon
    degeneration when injured
   Resveratrol is a small molecule
    that can activate NAD production
    and cross blood-brain barrier

Treatment with growth factors

   Defective VEGF has been shown to lead to
    neuron degeneration
   Treatment with VEGF can delay onset and slow
    progression of ALS in mice
   IGF-1 has also been successful in extending life
    span of mice with motor neuron disease
   How do we get these larger molecules into the
    central nervous system?

Other treatments

   Stems cells - can migrate to site of damaged
    neurons and release important growth factors
   RNAi - can slow down ALS by shutting down
    defective SOD1 using RNAi
   Exercise - can stimulate new neuron growth
    and increase levels of growth factors
   Drugs - Riluzole is first FDA approved drug
    treatment of ALS and works by decreasing the
    release of glutamate

The future of ALS research
   Various studies have reported gene mutations
    of TDP-43 in both rare familial ALS and
    sporadic ALS cases
   Mutated TDP-43 can form cellular aggregates
   Little is known about normal function, but
    seems to play a role in proper RNA metabolism
   Since it connects both familial and sporadic
    ALS, TARDBP may become a more important
    topic of research than SOD1

References
   Aebischer P, Kato AC. Playing Defense Against Lou Gehrig’s Disease. Scientific American.
    2007 Nov: 86-93.
   Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation
    prevent axonal degeneration. Science 2004 305:1010-1013.

   Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein
    JD, Borchelt DR, Price DL, Cleveland DW. ALS-linked SOD1 mutant G85R mediates damage to
    astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron.
    1997 Feb;18(2):327-38.

   Cleveland DW, Rothstein JD. From Charcot to Lou Gehrig: deciphering selective motor neuron
    death in ALS. Nat Rev Neurosci. 2001 Nov;2(11):806-19.
   Julien JP. ALS: astrocytes move in as deadly neighbors. Nat Neurosci 2007;10:535–537.

   Kanekura K, Suzuki H, Aiso S, Matsuoka M. ER Stress and Unfolded Protein Response in
    Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2009;39:81–89
   Kaspar BK, Frost LM, Christian L, Umapathi P, Gage FH. Synergy of insulin-like growth factor-1
    and exercise in amyotrophic lateral sclerosis. Ann Neurol. 2005 May;57(5):649-55.

   Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes
    expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat
    Neurosci. 2007 May;10(5):615-22. Epub 2007 Apr 15.

References
   Rothstein JD. Current Hypotheses for the Underlying Biology of Amyotrophic Lateral Sclerosis.
    Ann Neurol 2009;65 (suppl):S3–S9
   Spreux-Varoquaux O, Bensimon G, Lacomblez L, et al. Glutamate levels in cerebrospinal fluid
    in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric
    detection in a large cohort of patients. J Neurol Sci 2002;193:73–78.

   Valdmanis PN, Rouleau GA. Genetics of familial amyotrophic lateral sclerosis. Neurology
    2008;70;144-152
   Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM,
    Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu
    IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu
    CE. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic
    and histopathological analysis. Lancet Neurol. 2008 May;7(5):409-16. Epub 2008 Apr 7.

   Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, Hatfield G, Koliatsos VE. Human neural stem
    cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation. 2006.
    82(7):865–875.

   “About ALS.” ALS Association. Sept. 2008. Web. 20 April 2009.
   “Amyotrophic Lateral Sclerosis Fact Sheet.” National Institute of Neurological Disorders and
    Stroke. National Institutes of Health. April 2003. Web. 20 April 2009.