The downward spiral of tau and autolysosomes: A new hypothesis in neurodegeneration.

2012·0.57 MB·English

by  Ambegaokar, Suren S.

Autophagy8:7,1144–1145;July2012;G2012LandesBioscience
The downward spiral of tau and autolysosomes
A new hypothesis in neurodegeneration
Suren S. Ambegaokar and George R. Jackson*
.
DepartmentofNeurology;UniversityofTexasMedicalBranch;Galveston,TXUSA e
t
u
A growing body of research has strong modifiers of neurodegeneration b
connected autophagy to neuro- using an in vivo model expressing human ri
t
degenerative diseases such as Alzheimer MAPT in Drosophila. Several parts of s
disease (AD). In autopsied AD brain, the autophagy system including auto- i
d
large multivesicular bodies accumulate phagosome induction (Atg6), lysosomal

in neurons. Knockout mice deficient for acidification (Vha14) and autolysosome t
o
key autophagy genes demonstrate age- formation(white,brown,rosy)wereidenti- n
dependent neurodegeneration. Most fied in our screen. Other groups have
o
neurodegenerative diseases are charac- shown similar results with MAPT toxicity
D
terized by accumulation of insoluble and lysosomal associated genes, including

protein species; the type of protein and benchwarmer and the vacuolar ATPase .
e
the location of aggregates within the subunit v0a1.
c
nervous system help to define the type Although autophagy has been impli-
n
ofdisorder.Ithasbeenhypothesizedthat cated in other proteinopathies, use of the
e
theinabilitytodegradesuchaggregatesis same modifier alleles did not modify
i
c
a major causative factor in neuronal polyglutamine-induced degeneration in
s
dysfunctionandeventualneuronaldeath. our experiments. This may suggest a
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As neurons are postmitotic and thus specific, or perhaps a more sensitized,
i
B
cannot regenerate themselves, mecha- effect of autophagy dysregulation on
nisms of protein clearance have received MAPT pathology. The MAPT protein s
muchattentioninthefield.Thefunction has several serine, threonine and tyrosine e
of the ubiquitin-proteasome system residues that can be phosphorylated, the d
(UPS) is impaired in models of neuro- majority of which decrease the binding n
degeneration, and overexpression of affinity of MAPT to microtubules. As a
chaperone proteins, such as those in autophagosomes and lysosomes rely on L

the HSP70 family, leads to beneficial microtubule-basednetworksfortrafficking 2
Keywords: MAPT/tau, Alzheimer disease, effects in many models of protein- and eventually merge to form autolyso- 1
Drosophila, microtubule, phosphorylation opathies. Recently, studies of the effects somes, a link between MAPT, micro- 0
of autophagy as a clearance mechanism tubule trafficking and autolysosome 2
Submitted: 04/10/12
have uncovered compelling evidence formation can be made. In AD and other ©
Revised: 04/25/12 that inducing autophagy can alleviate tauopathies, MAPT is hyperphosphory-
Accepted: 04/25/12 many pathogenic and behavioral symp- lated, which has led to the prevailing
toms in animal and cellular models of hypothesis that increased phosphorylation
http://dx.doi.org/10.4161/auto.20515
neurodegeneration. of MAPT is the root cause of pathology,
*Correspondenceto:GeorgeR.Jackson;
causing decreased binding of MAPT to
Email:[email protected]
microtubules, which leads to destabilized
MAPT/tau is expressed predominantly in microtubule networks and ensuing traf-
Punctumto:AmbegaokarSS,JacksonGR.
axons where it binds to and stabilizes ficking deficits within diseased neurons.
Functionalgenomicscreenandnetworkanalysis
revealnovelmodifiersoftauopathydissociated microtubules. However, insoluble aggre- However, previous work from our lab
fromtauphosphorylation.HumMolGenet2011; gates of MAPT are found in several types has shown equivalent or increased toxicity
20:4947–77;PMID:21949350;http://dx.doi.org/10. of neurodegenerative diseases. Our report using phosphorylation-resistant MAPT
1093/hmg/ddr432
identified several autophagy genes as mutants. These isoforms have increased
1144 Autophagy Volume8Issue7
AUTOPHAGICPUNCTUM
bindingaffinitytotubulinascomparedwith
wild-typeMAPTinvivo.Thisindicatesthat
whenMAPTcannotdissociatefrommicro-
tubulesitisequallyormoretoxicthanwhen
MAPT is hyperphosphorylated and unable
tobindtomicrotubules.MAPThasamuch
higher binding affinity for tubulin then
eitherkinesinordynein,themotorproteins
needed for microtubule trafficking. Thus,
an alternate hypothesis can be put forward
that increased accumulation of soluble
MAPT outcompetes binding of motor .
e
proteins to microtubule tracks, in what
t
may be termed a “hyperbound” state of u
MAPT to microtubules. Lack of motor b
protein binding to microtubule tracks will ri
t
causemajordefectsintraffickingandaxonal s
transport. Of significant importance would i
d
bedisruptionofthemergingofautophago-

somes and lysosomes to form autolyso- ot
Figure1.Severalfactorscancontributetoreducedlysosomalandotherproteindegradation
somes. This would result in increased n
mechanisms.Oncepastapointofequilibrium,apositivefeedbackloopofMAPTaccumulationand
autophagosome production but without decreasedautolysosomefunctionisinitiatedthatcausesprogressiveworseningofreducedprotein o
the necessary acidic environment or pro- clearanceandimpairedaxonaltransport,whichmayexplainseveralphenomenaofneurodegenera-
D
teases found within lysosomes to clear the tivetauopathies.HyperphosphorylationofMAPTandinsolubleMAPTaggregationareby-productsin
contentsofautophagosomes.Disruptionof thismodelthatmayfurtherimpairproteindegradationprocessesorcauseotherdeleteriouseffects. .
e
autolysosomal formation would lead to
c
decreased degradation of a number of If we focus on increased levels of MAPT Other genetic and environmental factors,
n
proteins including MAPT. More MAPT as the main starting point, this too may along with possible effects from β-amyloid
e
would accumulate, leading to further also be due to autophagy/lysosomal (Aβ), can also contribute to reduced
i
“hyperbound” MAPT and still further dysfunction. MAPT can be degraded by proteolytic efficiency. c
s
trafficking blocks, inducing a downward several processes/proteins, including pro- In this model, several factors associated
o
spiral of impaired microtubule trafficking teases, the UPS, and cathepsin cleavage in with neurodegeneration, including the
i
B
and increased MAPT accumulation lysosomes. Impairment in any of these soluble oligomers, oxidative stress, mito-
(Fig.1). In this hypothesis, increased or processes could lead to reduced turnover chondrial dysfunction, excitotoxicity, s
“hyper” phosphorylation of MAPT is not andincreasedaccumulationofMAPT.The neurotrophins and cytokines, to name a e
the driving force of toxicity, but rather a probability of such impairments increases few,arenotaddressed.However,theroleof d
cellulardefensivemechanismtoalleviatethe with cellular and organismal age, and as autophagy in tauopathies and other neuro- n
burdenof“hyperbound”MAPTdisrupting neurons are postmitotic and ostensibly degenerativediseaseswillcontinuetobethe a
microtubuletrafficking. survive as long as the organism in which focusofmuchresearchinthenearfuture,as L

However,atriggerisneededtoinducea they function, neurons are particularly the processes of neuronal health, protein 2
“hyperbound”stateofMAPT.Thismaybe susceptible to reduced protein turnover turnover, and microtubule regulation 1
from either increased levels of soluble efficiency. This may also explain, in part, appear to be closely tied to one another. 0
MAPT or decreased ability to reduce the the late age of onset of most tauopathies We hope the model we provide serves to 2
bindingaffinityofMAPTformicrotubules. andtheprogressivedegenerationthereafter. addfurtherstimulustothisdiscussion. ©
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