Transcript Understanding physiologic changes in ataxia

Understanding physiologic
changes in ataxia
Vikram G. Shakkottai
Cells of the cerebellum
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
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
How does the cerebellum work?
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.
Why study cerebellar physiology?
Ataxic channelopathies
Disorder
Ion channel mutation (gene/protein)
SCA6
SCA13
SCA15
Episodic ataxia 1
Episodic ataxia 2
Episodic ataxia 5
SMEI
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
Disorder
Ion channel involved
SCA27
SCA5
DRPLA
Episodic ataxia 6
Paraneoplastic
cerebellar
ataxia
Nav1.6
Ionotropic glutamate receptors
Ionotropic glutamate receptors, GABAA receptors
Ionotropic glutamate receptors
Cav2.1
Ataxia from ion-channel mutations
Ataxic channelopathies
Disorder
Ion
channel
(gene/protein)
mutation 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
No channel mutation but channels
involved
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
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
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)?
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
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?
EA1
wikipedia
Basket cell showing axon branch points
How does acetazolamide work?
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
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
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
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
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
Paraneoplastic cerebellar ataxia
• Cerebellar ataxia sometimes occurs in
association with Lambert–Eaton 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
Paraneoplastic cerebellar ataxia
• When applied to cerebellar slices, an
antibody directed againt Cav2.1 reduced
synaptic transmission at the parallel fiber–
Purkinje cell synapse
• An anti-Cav2.1 antibody conferred an
ataxic phenotype by passive transfer in
mice
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
Postulated mechanism for altered physiology and ataxia