Understanding physiologic changes in ataxia

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Understanding physiologic changes in ataxia

• Vikram G. Shakkottai

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Cells of the cerebellum
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Physiologic features of cerebellar neurons

• Pacemaker neurons Purkinje and DCN neurons
• Neurotransmitter systems GABA projection neurons
  (Purkinje neurons)
• Glutamatergic projection neurons (DCN neurons)
• Interneurons GABA Golgi, Basket, Stellate,
  Lugaro. Glutamate UBN

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Cerebellar circuitry

• Cerebellar Input
• Climbing fibers Inferior olive
• Mossy fibers All other input
• Cerebellar output
• DCN projections
• Vestibulocerebellum- direct projections from PC
  to vestibular nuclei

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How does the cerebellum work?
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Why bother understanding Physiologic changes in
Ataxia?

• Mutations in ion channels. Neuronal dysfunction
  from perturbed channel activity
• Perturbations in ion channel physiology in the
  absence of a primary channel defect
• Novel therapeutic targets for symptomatic
  treatment of ataxia.

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Why study cerebellar physiology?
Ataxic channelopathies Ataxic channelopathies
Disorder SCA6 SCA13 SCA15 Episodic ataxia 1 Episodic ataxia 2 Episodic ataxia 5 SMEI Ion channel mutation (gene/protein) CACNA1A/Cav2.1 KCNC3/Kv3.3 ITPR1/IP3 receptor KCNA1/Kv1.1 CACNA1A/Cav2.1 CACNB4/Cav2.1 auxiliary subunit SCN1A/Nav1.1

Ataxias associated with channel dysfunction without channel mutations Ataxias associated with channel dysfunction without channel mutations
Disorder SCA27 SCA5 DRPLA Episodic ataxia 6 Paraneoplastic cerebellar ataxia Ion channel involved Nav1.6 Ionotropic glutamate receptors Ionotropic glutamate receptors, GABAA receptors Ionotropic glutamate receptors Cav2.1
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Ataxia from ion-channel mutations
Ataxic channelopathies Ataxic channelopathies Ataxic channelopathies
Disorder Ion channel mutation (gene/protein) Type of mutation
SCA6 CACNA1A/Cav2.1 ?Haploinsufficiency/ ?Gain of function
SCA13 KCNC3/Kv3.3 Dominant-negative
SCA15 ITPR1/IP3 receptor Dominant negative
Episodic ataxia 1 KCNA1/Kv1.1 Dominant-negative
Episodic ataxia 2 CACNA1A/Cav2.1 Haploinsuffiency
Episodic ataxia 5 CACNB4/Cav2.1 Auxiliary subunit ?Haploinsufficiency/ ?Dominant negative
SMEI SCN1A/Nav1.1 Haploinsufficiency
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No channel mutation but channels involved
Ataxias associated with channel dysfunction without channel mutations Ataxias associated with channel dysfunction without channel mutations
Disorder Ion channel involved
SCA27 Nav1.6
SCA5 Ionotropic glutamate receptors
DRPLA Ionotropic glutamate receptors, GABAA receptors
Episodic ataxia 6 Ionotropic glutamate receptors
Paraneoplastic Cerebellar ataxia Cav2.1
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SCA6

• CAG repeat/polyglutamine disorder
• Expansion of a polyglutamine tract in the
  carboxyl terminus (C-terminus) of the P/Q type
  voltage-gated calcium channel alpha subunit,
  Cav2.1
• A relatively pure cerebellar syndrome, SCA6 is
  notable for selective degeneration of cerebellar
  Purkinje neurons

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SCA6

• Precise mechanism by which the altered Cav2.1
  protein causes ataxia remains uncertain
• Altered channel function (haploinsufficiency)?
• Production of an aberrant C-terminal fragment
  (gain of function)?

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SCA13

• Mutations in the KCNC3 gene encoding the
  voltage-gated potassium channel protein, Kv3.3
• Purkinje neurons in null mice display broader
  action potentials, fail to sustain high frequency
  firing in response to injected current, and have
  reduced burst frequency in response to climbing
  fiber stimulation
• The cerebellar atrophy seen in patients with
  SCA13 has been hypothesized to be due to
  increased calcium entry into Purkinje neurons
  secondary to the spike broadening seen in the
  null mice

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Episodic ataxia 1 (EA1)

• Mutations in the voltage-gated potassium
  channel, KCNA1 (Kv1.1)
• Purkinje neurons show increased GABAergic
  inhibitory postsynaptic currents (IPSCs)
• Kv1.1 normally hyperpolarizes axon branch points
  of Basket neurons, preventing some action
  potentials from reaching the presynaptic terminal
• More action potentials to invade presynaptic
  terminal?

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EA1
wikipedia
Basket cell showing axon branch points
How does acetazolamide work?
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EA2 and EA5

• Mutations in CACNA1A
• EA2 is allelic with SCA6 and familial hemiplegic
  migraine
• More than 20 CACNA1A mutations have been
  identified which result in a truncated,
  nonfunctional protein
• Attacks of ataxia and migraine-like symptoms that
  may be precipitated by physical and emotional
  stress, coffee or alcohol
• Signs of cerebellar dysfunction can be present
  between the paroxysmal episodes
• Another form of episodic ataxia, EA5, is caused
  by mutations in CACNB4 which encodes an auxiliary
  beta subunit of Cav2.1

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EA2

• Mutations in the P/Q-type voltage-gated calcium
  channel, Cav2.1, leads to reduced calcium current
  density
• Impaired synaptic transmission at the parallel
  fiber-Purkinje neuron synapse
• Reduced precision of intrinsic pacemaker firing
  by Purkinje neurons

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EA2

• A calcium-activated potassium channel opener
  improves motor behavior in mice
• Acetazolamide prevents or attenuates attacks in
  50 to 75 of patients.
• Acetazolamide-induced changes in intracellular pH
  and the resulting change in potassium channel
  conductance may explain the therapeutic effect of
  the drug

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SCA27

• SCA27 was first described in a Dutch pedigree
  manifesting childhood-onset postural tremor and
  slowly progressive ataxia beginning in young
  adulthood
• Orofacial dyskinesias, postural limb tremor,
  disorders of executive function and non-verbal
  memory often occur
• Mutations in the fibroblast growth factor 14
  (FGF14) gene cause SCA27

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SCA27

• Although SCA27 is not caused by an ion channel
  mutation, the ataxic phenotype in this disorder
  results from perturbed expression of
  voltage-gated sodium channels in cerebellar
  neurons
• Most Purkinje neurons in a mouse model of SCA27
  do not fire spontaneously
• There is reduced expression of Nav1.6 in Purkinje
  neurons
• Mutant FGF14 protein fails to interact with
  sodium channel subunits, and interferes with the
  interaction between wild-type FGF14 and
  voltage-gated sodium channel subunits in a
  dominant manner

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Paraneoplastic cerebellar ataxia

• Cerebellar ataxia sometimes occurs in association
  with LambertEaton myasthenic syndrome (LEMS)
• LEMS immune-mediated disorder of the
  neuromuscular junction associated with antibodies
  directed against the voltage gated P/Q type
  calcium channel, Cav2.1
• Cerebellar symptoms were in a recent study
  present in 9 of 97 patients with LEMS, in nearly
  all cases associated with small cell lung cancer

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Paraneoplastic cerebellar ataxia

• When applied to cerebellar slices, an antibody
  directed againt Cav2.1 reduced synaptic
  transmission at the parallel fiberPurkinje cell
  synapse
• An anti-Cav2.1 antibody conferred an ataxic
  phenotype by passive transfer in mice

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How about the degenerative ataxias?

• Neuronal loss does not explain all the phenotypic
  changes in the degenerative ataxias
• For example mouse models of SCA1 show a
  neurological phenotype prior to significant
  neuronal cell loss
• Expression of expanded (pathogenic) ataxin-3 in
  differentiated neural cells caused
  electrophysiologic dysfunction preceding the
  onset of nuclear inclusions and ultrastructural
  morphological changes

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Postulated mechanism for altered physiology and
ataxia