Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease

Grosso, Ambra Del; Angella, Lucia; Tonazzini, Ilaria; Moscardini, Aldo; Giordano, Nadia; Caleo, Matteo; Rocchiccioli, Silvia; Cecchini, Marco

doi:10.1016/j.nbd.2019.05.011

Cited by 33 publications

(67 citation statements)

References 55 publications

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“…HSP70 together with the constitutively expressed member of the HSP70 family (heat-shock cognate 70, HSC70) are central players in protein folding and proteostasis control, and thus constitute the first cellular line of defense against misfolded proteins (Hartl, Bracher, & Hayer-Hartl, 2011;Scheufler et al, 2000). Interestingly, the high abundance of HSP7C we demonstrated in TW is in agreement with the data from Del Grosso et al, showing autophagy dysregulation as a key mechanism in the molecular pathogenesis of Krabbe disease (Del Grosso et al, 2019). In fact, it is known that the macro-autophagy, involving the engulfment of ubiquitinylated and aggregated proteins, is induced by the recognition of misfolded proteins through molecular chaperone complexes containing HSP7C (Hartl et al, 2011).…”

Section: Analysis Of Protein Synthesis and Degradation Markerssupporting

confidence: 92%

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

Landi

Luddi

Bianchi

et al. 2019

J of Neuroscience Research

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In Krabbe disease, a mutation in GALC gene causes widespread demyelination determining cell death by apoptosis, mainly in oligodendrocytes and Schwann cells. Less is known on the molecular mechanisms induced by this deficiency. Here, we report an impairment in protein synthesis and degradation and in proteasomal clearance with a potential accumulation of the misfolded proteins and induction of the endoplasmic reticulum stress in the brain of 6-day-old twitcher mice (TM) (model of Krabbe disease). In particular, an imbalance of the immunoproteasome function was highlighted, useful for shaping adaptive immune response by neurological cells. Moreover, our data show an involvement of cytoskeleton remodeling in Krabbe pathogenesis, with a lamin meshwork disaggregation in twitcher oligodendrocytes in 6-day-old TM. This study provides interesting protein targets and mechanistic insight on the early onset of Krabbe disease that may be promising options to be tested in combination with currently available therapies to rescue Krabbe phenotype.

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Section: Analysis Of Protein Synthesis and Degradation Markerssupporting

confidence: 92%

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

Landi

Luddi

Bianchi

et al. 2019

J of Neuroscience Research

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“…Codice 535/2018-PR; official starting date: 9 July 2018). For genotyping purpose, mice genomic DNA was extracted from clipped tails of mice at post-natal day (PND) 10 to 15 (EUROGOLD Tissue-DNA Mini Kit, EUROCLONE), as previously done by us ( 45 ). The genetic status of each mouse was later determined from the genome analysis of the TWI mutation, as reported from Sakai and co-workers ( 46 ).…”

Section: Methodsmentioning

confidence: 99%

Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease

et al. 2019

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Lysosomal storage disorders (LSDs) result from an enzyme deficiency within lysosomes. The systemic administration of the missing enzyme, however, is not effective in the case of LSDs with central nervous system (CNS)-involvement. Here, an enzyme delivery system based on the encapsulation of cross-linked enzyme aggregates (CLEAs) into poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) functionalized with brain targeting peptides (Ang2, g7 or Tf2) is demonstrated for Krabbe disease, a neurodegenerative LSD caused by galactosylceramidase (GALC) deficiency. We first synthesize and characterize Ang2-, g7- and Tf2-targeted GALC CLEA NPs. We study NP cell trafficking and capability to reinstate enzymatic activity in vitro. Then, we successfully test our formulations in the Twitcher mouse. We report enzymatic activity measurements in the nervous system and in accumulation districts upon intraperitoneal injections, demonstrating activity recovery in the brain up to the unaffected mice level. Together, these results open new therapeutic perspectives for all LSDs with major CNS-involvement.

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“…For example, autophagy was shown to be defective in Tay–Sachs disease due to either a reduction in the number of autophagosomes produced or the amount of autophagic flux; studies on pyrimethamine, a known pharmacological chaperone of β-hexosaminidase A, showed that the mechanism of action of pyrimethamine in reversing the defective lysosomal phenotype was by improving autophagy [ 207 ]. Autophagy dysregulation is also observed in Krabbe disease; expression of some fundamental autophagy markers (LC3, p62 and Beclin-1) was elevated in the brain and sciatic nerve of a murine model of the disease [ 90 ]. Treatment with rapamycin, an autophagy inducer, was shown to restore autophagy in vitro [ 90 ].…”

Section: Lipid Metabolism and Diseasesmentioning

confidence: 99%

“…Autophagy dysregulation is also observed in Krabbe disease; expression of some fundamental autophagy markers (LC3, p62 and Beclin-1) was elevated in the brain and sciatic nerve of a murine model of the disease [ 90 ]. Treatment with rapamycin, an autophagy inducer, was shown to restore autophagy in vitro [ 90 ].…”

Section: Lipid Metabolism and Diseasesmentioning

confidence: 99%

Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases

Kłoska

Węsierska

Malinowska

et al. 2020

IJMS

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This review discusses how lipophagy and cytosolic lipolysis degrade cellular lipids, as well as how these pathway ys communicate, how they affect lipid metabolism and energy homeostasis in cells and how their dysfunction affects the pathogenesis of lipid storage and lipid metabolism diseases. Answers to these questions will likely uncover novel strategies for the treatment of aforementioned human diseases, but, above all, will avoid destructive effects of high concentrations of lipids—referred to as lipotoxicity—resulting in cellular dysfunction and cell death.

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Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease

Cited by 33 publications

References 55 publications

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease

Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases

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