Neurodegeneration and Movement Control

• Oxidative Stress
• Mitochondrial Dysfunction
• Excitotoxicity and calcium
• Neurotrophic factors
• Microglia and cytokines

– Ion fluxes across the plasma membrane
– Activation of Ca2+-dependent proteases
– Mitochondrial disruption
– Loss of ATP
– Cellular swelling
– Preservation of nuclear DNA

– Cell shrinkage
– Maintenance of the plasma membrane
– Cytoskeletal depolymerization
– Fragmentation of nuclear DNA
– Requires protein synthesis

– Depletion of energy stores
– Failure of ion pumps
– Neuronal depolarization
– Increases in intracellular calcium
– Free radical formation
– Acidosis
– Protein aggregation
– ER Stress Response
– Autophagy

• Oxidative stress
• Axonal Injury
• Accumulation of Cytoskeletal Proteins
• Pathology presents as a result of cell death
• Age-related onset
• Disaster theory???

• Proteasome proteolyses ubiquitinated substrates
• It is an endopeptidase complex that can be compared to a ‘trash can’
• Undegradable protein aggregates play a role in a number of neurodegenerative diseases
– Polyglutamine repeats
– Parkin
• Uncleavable aggregates lead to cellular dysfunction and death

• Movement control operates primarily through the basal ganglia
• Anatomy and physiology of basal ganglia are extremely complicated
• Nobody really knows how it all works
• Underlying hypothesis do exist and are testable
• Much of what we do know comes from the study of disease

• Receives input from the Cerebral cortex
• Striatum (including caudate nucleus and putamen)
• Global Pallidus (lateral and medial)
• Subthalamic nucleus
• Substantia nigra (pars compacta and pars reticulata)
• Output goes from the thalamus back to the cerebral cortex

• γ-amino butyric acid (GABA)
• Acetylcholine (Ach)
• Dopamine (Da)
• Glutamate (Glu)
• Adenosine (Ad)
• Neurokinins (Substance P, SP)
• Opiod Peptides (endorphins/met-enkephalin, Enk)

• SNC - Substantia Nigra Compacta
• STN – Subthalamic nucelus
• LGP – Lateral Global Pallidus
• SNR – Substantia Nigra Reticulata
• MGP Medial Global Pallidus

• Direct movement control is the act of higher function to exact a positive change in activity (Start/Stop)
• Filled arrows are increased during movement control
• Open arrows are reduced during movement control
• Increased Glutamate outflow from Ventrolateral Thalamus leads to reinforcement of the decision to move.

• Indirect movement control is best thought of as the inhibition of non-required movement
• Thick with closed arrow (increased), Thin with open arrow (decreased)

• Dopamine Transporter
• Vesicular monoamine transporter
• Dopamine receptors
– Two families
– Five types
– D1 & 5 vs D2,3,4
• Monoamine oxidase (MAO)
• Catechol-O-Methyl Transferase (COMT)

• All types metabotropic receptors
• Two-main families
– D1-like - link to $G_\alpha s$- increase adenylate cyclase activity - indirect excitatory effect - D1 & D5
– D2-like - link to $G_\alpha i$ - increase phosphodiesterase activity - indirect inhibitory effect (induce IPSP) - D2, D3, & D4

• Pharmacological targeting of D-receptors forms the basis of many CNS drugs

• Anti-psychotics
– Typical (Haloperidol) and Atypical (Aripiprazole)

• Anti-emetics - metoclopramide
• Anti-arrythmics - procainamide
• Antidepressants - imipramine
• Anti-Parkinsonians - pramipexole

• Basal ganglia
• Movement control and Neurotransmission
• Dopaminergic Signaling
– Pathway
– Receptors
– Functions
• Hypo and Hyperkinetic Diseases
– Pathology
– Dopaminergics
– Other therapies

abnormally decreased mobility or motor function (both start and stop)

abnormally increased muscular activity

slowed ability to start or continue movement

irregular, unpredictable, and involuntary muscle jerks (distinct form Tics which are coordinated abnormal movements)

slow and writhing abnormal movements

abnormal posture resulting form tonic contractions

• Classic Hypokineticdisorder
• Associated dystonia
• Essential Tremor
• Young and Older onset forms of disease
• Five stages

• Environmental factors
– Exogenous toxins (MPTP)
– Trauma

• Genetic factors
– Low concordance rates
– Multiple potential targets
• Parkin, UCHL1, $\alpha$-synuclein, Leucine repeat rich kinase-2,
PTEN-induced kinase 1
• Mitochondrial DNA

• Italian kindred
– α-synuclein

• Parkin - E3 ubiquitin ligase
• UCHL1 – a deubiquitinating enzyme
• $\alpha$-synuclein – SNARE chaperone interacts with tubulin synaptic rearrangement
• Tau – microtubule associated protein
• Dardarin (LRRK2) – signaling protein that operates like Ras to control autophagy and induce apoptosis
• PTEN-induced kinase 1(PINK1) –serine/threonine kinase that is thought to protect cells from mitochondrial stress

• Carlsson (1957) showed DA in the striatum
• Reserpine in animals induced PD by striatal loss of DA
• Ehringer & Hornykielwicz (1960) DA i.v reduced akinesis of reserpine
• Cotzias (1967) found high dose oral levodopa effective in idiopathic PD.

• Peripheral vs central conversion
• Carbidopa
– Inhibitor of AAAD
– Unable to cross Blood Brain Barrier
– Decreases peripheral conversion
– Increases central effect and reduces peripheral side effects

• Choreas have been described for over 300 years
• Formally described in 1872 by George Huntington
• Occurs in 5 to 10 per 100,000 people
• Inherited as an autosomal dominant disorder
• Caused by trinucletoide repeats in gene IT15
• Disease usually starts in mid-thirties to mid-forties
• Personality change and adventitious movement develops into chorea, cognitive dysfunction and memory loss
• Death usually occurs as a result of secondary factors within 10 to 30 years

• Patients are often thin
– High metabolic rate??
• Striatal injection of NMDA agonists produces symptoms
• 3-nitropropionic acid (3-NP) complex II inhibitor produces striatal lesions

• Expressed in cytoplasm
• No clear function
• Binds to Huntingtin associated protein 1 (HAP1)
• Most common in NO synthesizing neurons
• Mutant form contains polyglutamine repeats (CAG)
• More repeats more severe disease
• Maybe caspase substrate
• Binds to Glyceraldehyde-3-phosphates dehydrogenase
• Polyglutamines bind to sugars causing aggregation

• NMDA antagonists
• Antioxidants (Omega-3 Fatty acids)
• Minocycline (apoptosis inhibitor)
• Neurotrophic growth factors (GDNF)
• Antidopaminergic (Tetrabenazine TBZ VMAT inhibitor)

• Inhibition of aggregation
– Disaccharides bind polyQ
– Trehalose

• Antipsychotics (Fluphenazine, D2 effect)
• Rapamycin (inhibit the kinase mTOR)

• Early in disease depressed, irritable, anxious, or psychotic
– Fluoxetine
– Carbamazepine
– Caution can impair mobility

• Large-amplitude chorea
– Reserpine
– Benzodiazepines

• Juvenile onset and rigidity
– DA agonists

• Disease onset usually occurs in mid-thirties to mid-fifties
• Presents as peripheral weakness and/or loss of function (heterogeneous presentation makes diagnosis difficulty)
• Leads to paralysis and death
• Disease progression is usually 2-3 years
• No known effective therapy

Guamanian ALS-PDC is a neurological disease that is characterized by a combination of symptoms of amyotrophic lateral sclerosis (ALS) and Parkinson's disease.

The older you are when diagnosed, the shorter you live afterward

More men are affected by ALS than women

It is believed that mutations in the SOD1 gene lead to the accumulation of toxic SOD1 protein aggregates in motor neurons, which ultimately results in the death of these neurons. This, in turn, leads to the progressive loss of muscle function and eventual paralysis, which are hallmark symptoms of ALS.

• ALS-FRS
– Functional rating scale
– Considers upper and lower motor neuron loss and specific functional effects
– Disease progression related to phenotypic presentation

• Ultrasound
– Can determine loss of motor unit density

• Electromyography
– Adverse events, fasiculations, bloackage events
– Disorder recruitment

• Pre-FALS Study
– Identify biomarkers

• Symptomatic
– BiPAP
– Mucolytic agents
– Antidepressants
– Mild Exercise

• Neuroprotection/Antioxidants
– Vitamin E
– Selegiline
– NAC

• Increased Mitochondrial Function
– Dexpramipexole

• Neurotrophic factors
– IGF-1
– Myotrophin

• Reduced Excitation
– Riluzole
• Increases ventilator free life
– Lamotrigine
• Voltage gated sodium channel blocker
– Ceftriaxone
• Increased glutamate uptake by astrocytic cells EAAT2 expression
– Retigabine
• Stimulate Potassium channel opening (hyperpolarize)

• Anti-inflammatory
– Mastinib
• CD117 tyrosine kinase inhibitor (myeloid cells)

• Sodium channel blocker
• High voltage calcium channel blocker
• NMDA receptor antagonist
• Antagonized by pertussis toxin
– Potential GPCR
• Metabolized in liver by P450 enzymes
– Potential hepatotoxicity
• Slows down progression of disease ?

• Tau-tubulin kinase inhibitors (TDP-43)

• Antisense oligos (C9orf72)

• Antisense FUS

• RAN antibodies