Dopamine, L-DOPA, catecholamines, TH, Nuur1 etc.

catecholamines (儿茶酚胺) is the collection name for three neurotransmitters: epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine.

L-DOPA is its precursor. Its corresponding drug is called levodopa.

L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase (TH).

Tyrosine cannot pass the BBB (blood brain barrier), but L-DOPA can.

L-DOPA can be converted to dopamine, which can be further converted to epinephrine (adrenaline), norepinephrine (noradrenaline).

Dopaminergic neurons can be divided into 11 cell groups according to where they located, using histochemical fluorescence method. It includes A8-A16, Aaq and Telencephalic group. Among that, A9 is where the substantia nigra pars compacta (SNpc) refers.

Number of TH-positive neurons in SN declines with age, while a-synuclein level increases with age. This inverse relationship is also seen in the surviving DA neurons of PD patients.

And it shows that the down-regulation of TH is linked to a reduction of expression of transcription factor called Nurr1 (orphan nuclear receptor, encoded by gene NR4A2).

Nurr1 is shown to regulate a category of nuclear-encoded mitochondrial genes. (http://www.ncbi.nlm.nih.gov/pubmed/23341612)

Neurodegenerative disease archive in Nature Review Neurology

A very good reading list about neurodegenerative disease, esp. at the 20th anniversary of the report that first identified a CAG repeat expansion in the huntingtin (HTT) gene as the cause of Huntington disease (HD):

http://www.nature.com/nrneurol/archive/subject_neuro_s16_082013.html

Among that, Huntington's disease related:

News and Views: Neurodegenerative disease: 'Fifty shades of grey' in the Huntington disease gene

Ferdinando Squitieri

doi:10.1038/nrneurol.2013.128

• Full Text
• PDF (142 KB)

Research Highlight: Neurodegenerative disease: Altered DNA methylation and RNA splicing could be key mechanisms in Huntington disease

Heather Wood

doi:10.1038/nrneurol.2013.23

• Full Text
• PDF (98 KB)

HDAC6, aggresome and Huntington's disease

I learned this piece of knowledge when I was reviewing the gene description for the update list of Factorbook (factorbook.org).

HDAC6 is a member of histone deacetylase/acuc/apha family. As the other member in the family, HDAC6 possesses histone deacetylase activity and represses transcription. But one other interesting function it has is to act as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.

Here is what I got from wikipedia page of aggresome:

The failure of polypeptides to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of misfolded proteins. Cells mainly deploy 3 mechanisms to counteract misfolded proteins:

1) up-regulating chaperones to assist protein refolding,
2) proteolytic degradation of the misfolded/damaged proteins involving ubiquitin–proteasome and autophagy–lysosome systems, and
3) formation of detergent-insoluble aggresomes by transporting the misfolded proteins along microtubules to a region near the nucleus.

Here is a figure illustrating the last two mechanisms:

Aggregated proteins are transported to the microtubule-organizing center (MTOC) by retrograde transport on microtubules (+ and - ends indicated) by dynein motor complexes. At the MTOC they are surrounded by a cage of intermediate filaments, such as vimentin (IF). Aggresomes have high concentrations of components of the ubiquitin–proteosome pathway of protein degradation, including HSP chaperonins, ubiquitin, and proteosomes. (Credit: http://www.nature.com/onc/journal/v24/n52/fig_tab/1209040f4.html)

While the mechanisms why these aggregates form (despite the existence of cellular machinery to recognize and degrade misfolded protein) and how they are delivered to cytoplasmic inclusions are not known, aggregation of misfolded protein in cytoplasmic inclusions is common to many age-related neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. It may be because these neurodegenerative diseases are mostly repeated expansion disease, they form aggregation with the inserted trinucleotide/peptide stretch. 

But why and how HDAC6 functions in the pathway of aggresome formation? What makes it different from other histone deacetylase?

Here is a recent paper might worthy to read:

HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
http://www.molecularneurodegeneration.com/content/8/1/7/

smallRNA in neurodegenerative diseases

Basic question: how does the small RNA function in neurodegenerative disease brain?

It's been shown that small RNAs (miRNA, piRNA, circular RNA) present in the brain. Recent researches even show that piRNA and circular RNA also expressed highly in brain tissues.

A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity.

Rajasethupathy P, Antonov I, Sheridan R, Frey S, Sander C, Tuschl T, Kandel ER.
Cell. 2012 Apr 27;149(3):693-707. doi: 10.1016/j.cell.2012.02.057.

The authors found several piRNA clusters highly expressed in Aplysia CNS, with the biogenesis pattern of piRNA in germline, including 5' U, piwi protein loaded, clustered, nuclear localized, sensitive to serotonin. They found that "the Piwi/piRNA complex facilitates serotonin-dependent methylation of a conserved CpG island in the promoter of CREB2, the major inhibitory constraint of memory in Aplysia, leading to enhanced long-term synaptic facilitation". They speculated that the piwi/piRNA complex methylates the promoter of target gene (CREB2 in this case) by first accessing its nascent transcript. Not sure if this also happened to other neuron-functioning genes, such as HES4 and HTT for HD.

Natural RNA circles function as efficient microRNA sponges.

Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J.
Nature. 2013 Mar 21;495(7441):384-8. doi: 10.1038/nature11993. Epub 2013 Feb 27.

Circular RNAs are a large class of animal RNAs with regulatory potency.

Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N.
Nature. 2013 Mar 21;495(7441):333-8. doi: 10.1038/nature11928. Epub 2013 Feb 27.

In these two new studies, the primary circular RNA of interest is an antisense transcript to CDR1 termed CDR1as (CDR1 antisense, used herein) or ciRS-7 (circular RNA sponge for miR-7). This RNA was validated by rigorous bioinformatic and molecular studies. Seventy-four copies of a miR-7 binding site are present in this circular RNA owing to the presence of a tandem repeat in the transcribed sequence of CDR1as. These binding sites are conserved across eutherian (placental) mammals, whereas the intervening sequences generally are not.
(Cite: http://www.nature.com/mt/journal/v21/n6/full/mt2013101a.html)

It's interesting that the circular RNA discovered this year also anti-sense to the target/host gene. Would that be a general mechanism that neurodegenerative disease are controlled by the anti-sense RNA?


Another question: why the repeated peptide/trinucleotide insertion or expansion is a common feature for most neurodegenerative disease?

Here is the table for the at least 20 inherit neuro-diseases and the associated repeat insertion:

Disease	Main clinical features	Causal repeat (gene)	Repeat location	Mechanism or category	Comments
DM1	Muscle weakness, myotonia, cardiac-endocrine-GI disease, MR	CTG (DM1, also known as DMPK)	3′ UTR	RNA GOF	A very common form of muscular dystrophy
DM2	Muscle weakness, myotonia, cardiac-endocrine-GI disease	CTG (ZNF9, also known as CNBP)	Intron	RNA GOF	A striking phenocopy of DM1
DRPLA	Seizures, choreoathetosis, ataxia, cognitive decline	CAG (ATN1)	Coding region	Polyglutamine GOF	Very rare, most patients are in Japan
FMR1	MR, facial dysmorphism, autism	CGG (FMR1)	5′ UTR	Hypermethylation of promoter, LOF	Most common inherited MR
FMR2	MR, hyperactivity	GCC (FMR2)	5′ UTR	LOF	Needs to be ruled out in X-linked MR
FRDA	Ataxia, sensory loss, weakness, diabetes mellitus, cardiomyopathy	GAA (FXN)	Intron	LOF, phenocopy of mitochondrial disease	Most common inherited ataxia in Caucasian ethnicity
FXTAS	Ataxia, intention tremor, parkinsonism	CGG (FMR1)	5′ UTR	RNA GOF	Premutation carriers only
HD	Chorea, dystonia, cognitive decline, psychiatric disease	CAG (HTT)	Coding region	Polyglutamine GOF	One of the most common inherited diseases in humans
HDL2	Chorea, dystonia, cognitive decline	CTG (JPH3)	3′ UTR, coding region	RNA GOF, poly-amino acid GOF and/or LOF?	A striking phenocopy of HD
Myoclonic epilepsy of Unverricht and Lundborg	Photosensitive myoclonus, tonic–clonic seizures, cerebellar degeneration	CCCCGCCCCGCG (CSTB)	Promoter	LOF	Rare autosomal recessive disorder found in Finland and N. Africa
OPMD	Eyelid weakness, dysphagia, proximal limb weakness	GCG (PABPN1)	Coding region	Polyalanine GOF	Modest expansion causes disease
SBMA	Proximal limb weakness, lower motor neuron disease	CAG (AR)	Coding region	Polyglutamine GOF	Phenotype includes LOF androgen insensitivity
SCA1	Ataxia, dysarthria, spasticity, ophthalmoplegia	CAG (ATXN1)	Coding region	Polyglutamine GOF	Accounts for 6% of all dominant ataxia
SCA2	Ataxia, slow eye movement, hyporeflexia, motor disease, occasional parkinsonism	CAG (ATXN2)	Coding region	Polyglutamine GOF	ATXN2 protein may not reside in the nucleus
SCA3	Ataxia, dystonia, lower motor neuron disease	CAG (ATXN3)	Coding region	Polyglutamine GOF	Most common dominant ataxia
SCA6	Ataxia, dysarthria, sensory loss, occasionally episodic	CAG (CACNA1A)	Coding region	Polyglutamine GOF	Causal gene encodes a subunit of a P/Q-type Ca2+ channel
SCA7	Ataxia, dysarthria, cone-rod dystrophy retinal disease	CAG (ATXN7)	Coding region	Polyglutamine GOF	Clinically distinct as patients have retinal disease
SCA8	Ataxia, dysarthria, nystagmus, spasticity	CTG/CAG (ATXN8)	Untranslated RNA, coding region	RNA GOF and polyglutamine GOF	Many cases of reduced penetrance
SCA10	Ataxia, dysarthria, seizures, dysphagia	ATTCT (ATXN10)	Intron	RNA GOF?	Huge repeats; only Mexican ancestry?
SCA12	Tremor, ataxia, spasticity, dementia	CAG (PPP2R2B)	Promoter, 5′ UTR?	Unknown	Causal gene encodes a phosphatase
SCA17	Ataxia, dementia, chorea, seizures, dystonia	CAG (TBP)	Coding region	Polyglutamine GOF	Causal gene encodes a common transcription factor (TBP)
Syndromic/non-syndromic X-linked mental retardation	MR alone, with seizures or with dysarthria and dystonia	GCG (ARX)	Coding region	Probably LOF	Associated with West syndrome or Partington syndrome
AR, androgen receptor; ARX, aristaless-related homeobox; ATN1, atrophin 1; ATXN, ataxin; CACNA1A, voltage-dependent P/Q-type calcium channel subunit α-1A; CSTB, cystatin B; DM, myotonic dystrophy; DMPK, DRPLA, dentatorubral-pallidoluysian atrophy; FMR1, fragile X mental retardation syndrome; FMR2, fragile X E mental retardation; FRDA, Friedreich's ataxia; FXN, frataxin; FXTAS, fragile X tremor ataxia syndrome; GI, gastrointestinal; GOF, gain of function; HD, Huntington's disease; HDL2, Huntington's disease-like 2; HTT, huntingtin; JPH3, junctophilin 3; LOF, loss of function; MR, mental retardation; OPMD, oculopharyngeal muscular dystrophy; PABPN1, poly(A)-binding protein, nuclear 1; PPP2R2B, protein phosphatase 2 regulatory subunit B, β isoform; SBMA, spinal and bulbar muscular atrophy; SCA, spinocerebellar ataxia; TBP, TATA box-binding protein; ZNF9, zinc finger 9.

Ref: http://www.nature.com/nrg/journal/v11/n4/fig_tab/nrg2748_T1.html

Not only genes in the list, other genes like the CDR1 (Cerebellar Degeneration-Related) gene mentioned above also contains several hexapeptide repeats.

 CDS             387..1175
                     /gene="CDR1"
                     /gene_synonym="CDR; CDR34; CDR62A"
                     /note="Derived by automated computational analysis using
                     gene prediction method: BestRefseq."
                     /codon_start=1
                     /product="cerebellar degeneration-related antigen 1"
                     /protein_id="NP_004056.2"
                     /db_xref="GI:44889483"
                     /db_xref="CCDS:CCDS14670.1"
                     /db_xref="GeneID:1038"
                     /db_xref="HGNC:1798"
                     /db_xref="HPRD:02361"
                     /db_xref="MIM:302650"
                     /translation="MAWLEDVDFLEDVPLLEDIPLLEDVPLLEDVPLLEDTSRLEDIN
                     LMEDMALLEDVDLLEDTDFLEDLDFSEAMDLREDKDFLEDMDSLEDMALLEDVDLLED
                     TDFLEDPDFLEAIDLREDKDFLEDMDSLEDLEAIGRCGFSGRHGFFGRRRFSGRPKLS
                     GRLGLLGRRGFSGRLGGYWKTWIFWKTWIFWKTWIFRKTYIGWKTWIFSGRCGLTGRP
                     GFGGRRRFFWKTLTDWKTWISFWKTLIDWKTWISFWKTLIDWKI"