 Accumulation of abnormal protein that cause neurodegeneration
 Useful for the development and evaluation of medicines Neurodegenerative diseases: Aging and spread of abnormal protein Our disease models for screening
Candidate

Amyloid betaAlzheimer disease

CellularmodelTau

Alzheimer disease (AD)

Dementia with Lewy Bodies (DLB)
Parkinson disease (PD)

Frontotemporal lobar degeneration
Amyotropic Lateral Sclerosis (ALS)

Animalmodelalpha-synuclein

Screening

TDP-43

Goal(Jucker M. & Walker L. C., Nature, 2013)

Novel medicineTarget

 Cellular modelsTau“Accumulation” of abnormal protein as seen in patient’s brainTDP-43

alpha-synuclein Ex. Search for drug candidate
Abnormal protein
Transfection
Normal protein

Transformation

PlasmidNN

No aggregation

NAggregation

Selection of compound suppressing TDP-43 aggregation fromPrestwick Chemical Library
FACS(fluorescence activated cell sorting)No aggregation

Aggregation

Untreated cells (Control)
Treated cells＝Inhibition of aggregation

No aggregation(Nonaka et al., J Biol Chem. 2010)

Aggregation, Phosphorylation,
Ubiquitination

We found several candidate compounds thatinhibit aggregation of abnormal TDP-43

 Animal models
Tau
Human
αSyn

“Propagation” of abnormal protein as seen in patient’s brainalpha-synuclein
Injection into
wild-type mouse
There is no change in case of injectionof normal αSyn into mouse brain

HumanαSyn“Normal” αSyn istransformed into
“Abnormal” in vitro

AbnormalαSyn

Injection
into brain

Is abnormal αSyn transformed into
abnormal in mouse brain ?

Insoluble fraction

Biochemical analysis of mouse brain injected abnormal αSyn

Injected αSyn wasdisappeared
Endogenous αSyn wasaccumulated withphosphorylation andubiquitination

N

Human αSyn was transformed into mouse αSyn

NNNNNNNDementiaNN

 Lab’s web site Patents

Tokyo metro. Inst. Med. Sci. Dementia project
URL: http://www.igakuken.or.jp/dementia/

 Tdp-43-storing cell model, JP 5667872, US 8715643,9128081, EP 2272955 DE,FR,GB Papers

 Protein which can serve as nucleus for polymerization ofprotein polymer, cell having the polymer introduced
therein, and process for production of the cell, JP5665258, EP 1964918 DE,FR,GB・Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A,
Akiyama H, Hasegawa M. Pathological alpha-synuclein propagates
through neural networks. Acta Neuropathol Commun. 2014 Aug 6;2:88.
・ Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T,
Akiyama H, Mann DM, Hasegawa M. Prion-like spreading of pathological
α-synuclein in brain. Brain. 2013 Apr;136(Pt 4):1128-38.
・Nonaka T, Watanabe ST, Iwatsubo T, Hasegawa M. Seeded aggregationand toxicity of α-synuclein and tau: cellular models ofneurodegenerative diseases. J Biol Chem. 2010 Nov 5;285(45):34885-98.
・Nonaka T, Arai T, Buratti E, Baralle FE, Akiyama H, Hasegawa M.
Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS
and FTLD-U are recapitulated in SH-SY5Y cells. FEBS Lett. 2009 Jan22;583(2):394-400.
・Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M. Truncation andpathogenic mutations facilitate the formation of intracellular aggregatesof TDP-43. Hum Mol Genet. 2009 Sep 15;18(18):3353-64.

 The screening method of the neurodegenerative disease
therapeutics, JP 4948845
 Antibody binding specifically to tdp-43 aggregate, JP5439176, US 8940872, EP 2189526 BE,DE,FR,GB,NL Method for producing insoluble aggregate ofneurodegenerative-disease-related protein, CN
201280044001.5