The Yeast Model for Batten Disease: Mutations in
 btn1
 ,
 btn2
 , and
 hsp30
 Alter pH Homeostasis

Chattopadhyay, Subrata; Muzaffar, Neda E.; Sherman, Fred; Pearce, David A.

doi:10.1128/jb.182.22.6418-6423.2000

Cited by 59 publications

(49 citation statements)

References 29 publications

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“…In budding yeast, Btn1p, the yeast orthologue of CLN3, is a vacuolar protein (the vacuole carrying out some of the functions of the lysosomes of higher eukaryotic cells) and has been implicated in vacuolar homeostasis (Pearce et al, 1999b;Pearce et al, 1998) although the molecular basis for this has not been determined. In cells deleted for Btn1p, decreased arginine transport into the vacuole (Kim et al, 2003), which is dependent on a functioning vATPase and vacuole acidification, has been reported, but this is at odds with the decreased vacuolar pH also reported in budding yeast cells missing functional Btn1p (Chattopadhyay et al, 2000;Pearce et al, 1999b).…”

Section: Introductioncontrasting

confidence: 42%

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

Gachet

Codlin

Hyams

et al. 2005

Journal of Cell Science

100

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Section: Introductioncontrasting

confidence: 42%

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

Gachet

Codlin

Hyams

et al. 2005

Journal of Cell Science

100

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“…Later surveys found Btn2p is also induced by heat shock (47). Btn2p has been reported to be localized in the cytoplasm (48) and to late endosomes (49). We found that Btn2p was consistently concentrated in one or two dots close to the nucleus (17).…”

Section: Discussionmentioning

confidence: 52%

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

Wickner

Bezsonov

Bateman

2014

Proc. Natl. Acad. Sci. U.S.A.

120

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[URE3] is an amyloid prion of the Saccharomyces cerevisiae Ure2p, a regulator of nitrogen catabolism. Overproduction of Btn2p, involved in late endosome to Golgi protein transport, or its paralog Cur1p, cures [URE3]. Btn2p, in curing, is colocalized with Ure2p in a single locus, suggesting sequestration of Ure2p amyloid filaments. We find that most [URE3] variants generated in a btn2 cur1 double mutant are cured by restoring normal levels of Btn2p and Cur1p, with both proteins needed for efficient curing. (1-4). Ure2p normally functions as a soluble regulator of nitrogen catabolism (5, 6), and its conversion to the aggregated amyloid prion form produces inappropriate derepression of many genes of nitrogen catabolism, resulting in slightly slowed growth (7). Many [URE3] isolates have a severe toxic effect, producing extremely slowed growth (8). A single protein sequence can assume any of many different heritable/infectious forms with different biological properties and, one infers, different protein conformations. The parallel in-register β-sheet architecture of the [URE3] prion amyloid (9) can explain the templating properties of this prion (10) and the ability of the Ure2p amyloid to act as a gene with multiple alleles (4).[PSI+] is similarly an amyloid prion of Sup35p, a subunit of the translation termination factor [reviewed by Liebman and Chernoff (11)], and [PIN+] is a prion of Rnq1p, a protein of unknown function (12)(13)(14).Eukaryotic cells deal with protein aggregates in several ways, including resolubilization, degradation, sequestration, and combinations of these processes. Several organelles and systems have been recognized to play a role in these processes, including vacuoles (the yeast equivalent of the mammalian lysosomes), the ubiquitin-proteasome systems, the autophagy system, and the various chaperones.In mammalian cells the aggresome is a centrosomal structure to which aggregates are brought in a microtubule-dependent process (15). A yeast site near the spindle pole body (the yeast centrosome) collects huntingtin/polyQ aggregates in a process that depends on microtubule function, suggesting that this is the yeast aggresome (16). Bmh1p, a 14-3-3 protein, was found associated with huntingtin in yeast aggresomes, and bmh1Δ prevented aggresome accumulation of huntingtin (16).Btn2p and Cur1p were found to cure the [URE3] prion when overproduced (17). These proteins are paralogs, members of the Hook family, consistent with their similar effects, but Btn2 localized to a site next to the nucleus, whereas Cur1 was localized largely within the nucleus (17). During the curing process, those [URE3] cells having both Ure2p-GFP aggregates and Btn2-RFP dots show striking colocalization (17-19). Partial colocalization of Btn2-RFP with Sup35NM-GFP in a [PSI+] strain or with the huntingtin-like Q103-GFP were also observed (17), but overexpression of Btn2p or Cur1p did not cure [PSI+]. Doubly deleted btn2Δ cur1Δ strains show an elevated seed number of [URE3] and partial resistance to prion curing by dimethyl sul...

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“…Studies in yeast indicate roles in maintenance of vacuolar arginine levels, pH, and/or ion homeostasis (Pearce et al, 1999;Chattopadhyay et al, 2000;Kim et al, 2003Kim et al, , 2005. A recent report indicates that, similar to yeast cells, arginine transport into lysosomes is defective in JNCL patient-derived lymphoblasts (Ramirez-Montealegre and .…”

Section: Discussionmentioning

confidence: 99%

A Knock-In Reporter Model of Batten Disease

Eliason¹,

Stein²,

Mao³

et al. 2007

J. Neurosci.

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Juvenile neuronal ceroid lipofuscinosis is a severe inherited neurodegenerative disease resulting from mutations in CLN3 (ceroidlipofuscinosis, neuronal 3, juvenile). CLN3 function, and where and when it is expressed during development, is not known. In this study, we generated a knock-in reporter mouse to elucidate CLN3 expression during embryogenesis and after birth and to correlate expression and behavior in a CLN3-deficient mouse. In embryonic brain, expression appeared in the cortical plate. In postnatal brain, expression was prominent in the cortex, subiculum, parasubiculum, granule neurons of the dentate gyrus, and some brainstem nuclei. In adult brain, reporter gene expression waned in most areas but remained in vascular endothelia and the dentate gyrus. Mice homozygous for Cln3 deletion showed two hallmark pathological features of the neuronal ceroid lipofuscinosises: autofluorescent inclusions and lysosomal enzyme elevation. Moreover, CLN3-deficient reporter mice displayed progressive neurological deficits, including impaired motor function, decreased overall activity, acquisition of resting tremors, and increased susceptibility to pentilentetrazole-induced seizures. Notably, seizure induction in heterozygous mice was accompanied by enhanced reporter expression. This model provides us with the unique ability to correlate expression with pathology and behavior, thus facilitating the elucidation of CLN3 function and the pathogenesis of Batten disease.

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The Yeast Model for Batten Disease: Mutations in btn1 , btn2 , and hsp30 Alter pH Homeostasis

Cited by 59 publications

References 29 publications

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

A Knock-In Reporter Model of Batten Disease

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