Stem cell news: iPS细胞研究揭示帕金森发病机制

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University of Buffalo的Jian Feng教授利用parkin基因突变的帕金森患者细胞制造iPS细胞，发现这些iPS细胞分化为神经元时单胺氧化酶（Monoamine oxidases, MAO）水平升高，促进氧化应激，降低多巴胺的摄取，而修正parkin的表达后可逆转上述变化。
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Nifty stem-cell engineering sheds light on Parkinson's disease8 [% q! I( W4 {$ F& Q$ l$ g
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by Elizabeth Armstrong Moore February 9, 2012 3:03 PM PST3 k3 V- r) _7 N) M* I+ z
Researchers at the University at Buffalo may have taken a significant step toward unraveling the way Parkinson's disease assails the human nervous system--thanks in part to a nifty bit of stem-cell engineering.
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Scientists led by physiologist Jian Feng took skin cells from healthy control subjects and people with a particular type of Parkinson's disease and transformed them into a type of primordial cell--technically, an "induced pluripotent stem cell." Such iPS cells, as they're known, can be coaxed into developing as almost any type of cell in the body.
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& U7 d3 c4 T' F2 u! i) THere, they turned into brain cells. And the cells from the Parkinson's patients turned into brain cells that contained a mutated form of the "parkin" gene.
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" R" O' P) F& P2 fIt's normally almost impossible to study brain cells from live Parkinson's patients. But by generating these brain cells in their lab, the scientists were able to avoid invasive brain surgery and observe that mutations of the parkin gene interrupt dopamine behavior and produce more free radicals, thereby destroying dopamine neurons, which is what causes Parkinson's disease.7 W$ g4 x6 A( b: C4 A* C
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In 9 out of 10 Parkinson's cases, researchers don't understand why these neurons die. In the remaining 10 percent, however, the mutation of genes such as parkin is the known culprit. And while the study, published this week in the journal Nature Communications, may only be looking at this minority of Parkinson's cases, understanding how the parkin gene works is relevant to the disease as a whole.# ?7 }5 l% e9 N4 U6 \) q4 k% J

' B+ \( X9 N* a* JThe team's findings could help lead to a breakthrough in the development of a drug that, if it can mimic the protective function of parkin, has the potential to cure this and even other forms of Parkinson's.
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The team's method is also a breakthrough because, as Feng says in a school news release, looking inside the brain's complex circuitry has until now been too invasive: "Before this, we didn't even think about being able to study Parkinson's disease in human neurons."; Q7 e) z* w$ e( a! P; I8 j9 `7 O
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Human neurons are important because researchers believe they have unique vulnerabilities not seen in animals. (Feng adds that our large brains may require more dopamine to control bipedal, as opposed to quadrupedal, movement.)0 Z0 p: v# x: ^$ h0 B/ a* B
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The team at Buffalo first got a glimpse of how they might generate these neurons in 2007, when researchers in Japan became the first to turn human cells into IPS cells. These are similar to embryonic stem cells, but don't require the destruction of embryos, and instead can be created from the cells of a mature individual.+ @7 c( c/ h" W6 F: q& u) E) |( F
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This accomplishment, Feng says, is advancing not only the study of Parkinson's but other neurological diseases simply by enabling researchers to non-invasively study the disease at its cellular level. "It finally allowed us to obtain the material we needed to study the disease.". r4 ~2 ?$ ?  s  k" Q  D5 [

$ X6 {* z" ^4 @' p& W1 ~, ]" ABy turning these patients' skin cells into dopamine neurons with parkin mutations, Feng and his colleagues were able to see that, once mutated, these cells no longer control how dopamine behaves, which directly hinders what Feng calls the "neural computation" necessary for movement.8 f) H# m7 o3 X" g  i' P; K

! G& I4 |  z3 `, J9 sFurthermore, the cells are no longer able to control the production of monoamine oxidase (MAO), which can be toxic and, at high levels, appear to contribute to oxidative stress, which can kill dopamine neurons. Maintaining the protective function of parkin, then, could be key to finding a cure for Parkinson's disease.: h; T) Z( F" }; e: z
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Mirror
6 L5 ~- Z3 H9 |Stem cell hope for millions with Parkinson's disease) s; b; L% L% T

+ C4 X) f5 [4 R/ Z3 W7 L# ^+ zUS scientists have grown brain nerve cells from skin to study a form of the ­debilitating ­condition linked to the parkin gene$ [( g# x- I9 V) A9 `# i
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A stem cell experiment in Parkinson’s disease research may bring hope to sufferers.0 p( _9 I: C# j* s/ \! q9 Z1 S

, e9 Z% I* E1 |3 \* vUS scientists have grown brain nerve cells from skin to study a form of the ­debilitating ­condition linked to the parkin gene.
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The researchers believe it will give them a clue to how other forms of Parkinson’s develop allowing them to target better drugs at the debilitating disease.4 w; S; \- F" p* t( K: l: O4 D& m
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Such neurons used to be inaccessible as they lie deep in the brain, but the stem cell technology has solved the problem.6 f" v' R( ?: z1 L$ n. Z0 W% C
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“This is the first time that human dopamine neurons have ever been generated from Parkinson’s disease patients with parkin mutations,” says Jian Feng, PhD, professor of physiology and biophysics in the University of Buffalo School of Medicine and Biomedical Sciences, lead author of a study in the journal Nature Communications.
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The problem has been that human neurons live in a complex network in the brain and thus are off-limits to invasive studies, professor Feng said.
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Once Parkin is mutated it can’t control dopamine in the brain which supports brain calculations needed for our movement of arms and legs.4 j" d3 I, }2 y+ ]4 O

7 o. M7 @1 @9 V4 jJapanese scientists announced in 2007 they had converted human cells into pluripotent stem cells which can then be converted into any cell in the body.
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It meant skin cells of Parkinson’s patients could be turned into nerve cells allowing the disease to be studied in lab dishes.& l4 u: ?7 C" i! S' E7 y, h1 f* R
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“This new technology was a game-changer for Parkinson’s disease and for other neurological diseases,” said professor Feng. “It finally allowed us to obtain the material we needed to study this disease.”
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& a4 u+ v+ H/ d( |! l4 yDr Michelle Gardner, research development manager at Parkinson’s UK, said: “New stem cell technology which allows nerve cells to be made from adult skin cells is opening doors for research into Parkinson’s.
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% w. G1 P! K3 h0 ^* P  ]4 A“This study is particularly exciting because it describes for the first time how researchers have successfully generated nerve cells from people with a rare genetic form of Parkinson, linked to the parkin gene.”
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7 U* A+ ]& D0 O/ m  E5 K6 h! |The research also showed how inserting the correct form of the gene into the nerve cells got them working properly opening up hopes of new treatment.! a6 u, s8 Q3 _5 E* v# U& B& N$ c
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" P$ x& `; z0 PNature Communications | Article5 Q8 k0 J3 G: L9 A
Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells
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, j( U6 P- T1 {    * Houbo Jiang,1
% K) d* k- \; y9 D) U9 B    * Yong Ren,1
4 Y/ I$ N- `( v    * Eunice Y. Yuen,1
5 V8 Y; {  _5 c0 d- R- k    * Ping Zhong,1
, P6 l, _, s- ~; A' P    * Mahboobe Ghaedi,1
8 M0 ^( L3 c* _, E8 ~    * Zhixing Hu,1& d9 ?# \! M3 ]/ g' d4 [5 _+ l
    * Gissou Azabdaftari,2# r4 v; E4 o% j7 S) W  ?
    * Kazuhiro Nakaso,3
8 o8 y* J3 d: h0 T. C6 i$ e  F    * Zhen Yan12 `0 O1 P0 m% b' T. c/ }) j
    * & Jian Feng/ z+ M) L" |- a  A1 H

' p3 ^2 V- n+ c. d# ]4 S8 p8 v    Nature Communications
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5 {! ?) a- R# ?2 rArticle number:9 s7 _; `7 d- ]* ]! K6 n9 J0 n% a
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DOI:
1 O; k2 n/ I! Y# y" W    doi:10.1038/ncomms1669
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Received# ]. ?1 D. d6 n
    15 August 2011 3 B9 U( O2 N8 w; r- o
Accepted
9 @/ I$ E9 Z8 E1 [5 c, i    09 January 2012 ( ]  Z3 R  R- G1 `+ p& f
Published
: t) A6 s; e- T% J) d0 I& p    07 February 2012 * \* _: l" F0 ^

+ s0 }1 c& _6 b1 ]* Q  dParkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD.+ ?) d4 C8 u, {, c: N* o# w
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