Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects
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eLife Assessment
This study investigated mitochondrial dysfunction and the impairment of the ciliary Sonic Hedgehog signaling in Lowe syndrome (LS), a timely topic given the limited research in this area. The data from patient iPSC-derived neurons and a mouse model were collected using solid methods, but the evidence supporting key claims is incomplete, and some technical aspects fall short of expectations. Despite these limitations, the study provides a useful foundation for exploring the relationship between mitochondrial defects and primary cilia in neural development.
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Abstract
Human brain development is a complex process that requires intricate coordination of multiple cellular and developmental events. Dysfunction of lipid metabolism can lead to neurodevelopmental disorders. Lowe syndrome (LS) is a recessive X-linked disorder associated with proximal tubular renal disease, congenital cataracts and glaucoma, and central nervous system developmental delays. Mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase, lead to the development of LS. The cellular mechanism responsible for neuronal dysfunction in LS is unknown. Here we show depletion of mitochondrial DNA and decrease in mitochondrial activities result in neuronal differentiation defects. Increased astrocytes, which are secondary responders to neurodegeneration, are observed in neuronal (iN) cells differentiated from Lowe patient-derived iPSCs and an LS mouse model. Inactivation of cilia-related sonic hedgehog signaling, which organizes the pattern of cellular neuronal differentiation, is observed in an OCRL knockout, iN cells differentiated from Lowe patient-derived iPSCs, and an LS mouse model. Taken together, our findings indicate that mitochondrial dysfunction and impairment of the ciliary sonic hedgehog signaling pathway represent a novel pathogenic mechanism underlying the disrupted neuronal differentiation observed in LS.
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eLife Assessment
This study investigated mitochondrial dysfunction and the impairment of the ciliary Sonic Hedgehog signaling in Lowe syndrome (LS), a timely topic given the limited research in this area. The data from patient iPSC-derived neurons and a mouse model were collected using solid methods, but the evidence supporting key claims is incomplete, and some technical aspects fall short of expectations. Despite these limitations, the study provides a useful foundation for exploring the relationship between mitochondrial defects and primary cilia in neural development.
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Reviewer #1 (Public review):
Summary:
This study by Lo et al. seeks to explain the cellular defects underlying the brain phenotypes of Lowe syndrome (LS). There have been limited studies on this topic and hence this is a timely study.
Strengths:
Studies such as these can contribute to an understanding of the cellular and developmental mechanisms of brain disorders.
Weaknesses:
This study by Lo et al. seeks to explain the cellular defects underlying the brain phenotypes of Lowe syndrome (LS). There have been limited studies on this topic and hence this is a timely study.
The study uses two models: (1) an LS IOB knockout mouse and (2) neurons derived from iPSC lines from LS patients. These two models are used to present three separate findings: (1) altered mitochondria function, (2) altered numbers of neurons and glia in both models, and …
Reviewer #1 (Public review):
Summary:
This study by Lo et al. seeks to explain the cellular defects underlying the brain phenotypes of Lowe syndrome (LS). There have been limited studies on this topic and hence this is a timely study.
Strengths:
Studies such as these can contribute to an understanding of the cellular and developmental mechanisms of brain disorders.
Weaknesses:
This study by Lo et al. seeks to explain the cellular defects underlying the brain phenotypes of Lowe syndrome (LS). There have been limited studies on this topic and hence this is a timely study.
The study uses two models: (1) an LS IOB knockout mouse and (2) neurons derived from iPSC lines from LS patients. These two models are used to present three separate findings: (1) altered mitochondria function, (2) altered numbers of neurons and glia in both models, and (3) some evidence of altered Sonic Hedgehog signaling projected as a defect in cilia.
Conceptually, there are some problems of serious concern which must be carefully considered:
(1) The IOB mouse was very extensively phenotyped when it was generated by Festa et.al HMM, 2019. It does not have any obvious phenotypes of brain deficits although the studies in this paper were very detailed indeed.
(2) Reduced brain size is reported as a phenotype of the IOB mouse in this study. Yet over the many clinical studies of LS published over the years, altered brain size has not been noted, either in clinical examination or in the many MRI reports of LS patients.While reading through these results it is striking that the link between the three reported phenotypes is at least tenuous, and in fact may not exist at all. The link between mitochondria and neurogenesis is based on a single paper that has been cited incorrectly and out of context. There is no evidence presented for a link between the Shh signaling defect reported and the mitochondrial phenotype.
General comments
(1) The preparation of the manuscript requires improvement. There are many errors in the presentation of data.
(2) The use of references needs to be re-considered. Sometimes a reference is used when in fact the results included in that paper are the opposite of what the authors intend.
(3) The authors conclude the paper by claiming that mitochondrial dysfunction and impairments of the ciliary SHH contribute to abnormal neuronal differentiation in LS, but the mechanism by which this sequence of events might happen hasn't been shown.Final comments:
(1) Phenotype of increased astrocytes:
The phenotype of increased astrocytes in both the IOB mouse brain or iPSC-derived cultures iN cells requires clarification as one of the markers used as an astrocyte marker, BRN2, is commonly used as a neuronal marker. As LS is a neurodevelopmental disorder, and the phenotype in question is related to differentiation, it is crucial to shed light on the developmental timeline in which this phenotype is seen in the mouse brain.(2) Ciliary homeostasis:
Mitochondrial dysfunction in astrocytes has been shown to induce a ciliogenic program. However, almost the opposite is shown in this paper, with regards to ciliation. Morphology of the cilia was not assessed either, which is an important feature of ciliary homeostasis. The improper ciliary homeostasis here appears to be the improper Shh signalling, which has not been shown to be related to mitochondrial dysfunction. This leaves one wondering how exactly the different phenotypes shown in this paper are connected.(3) This paper lacks a clear mechanistic approach. While the data validates the 3 broad phenotypes mentioned, there is a lack of connection between these phenotypes or an answer to why these phenotypes appear. While the discussion attempts to shed light on this by referencing previous studies, some of the referenced studies show contradicting results. Hence, it would be beneficial to clarify these gaps with further experiments and address the larger question of the connection between the mitochondria, Shh signalling, and astrocyte formation.
(4) Most importantly, there is no mention of how the loss of OCRL, a 5-phosphatase enzyme, results in the appearance of the mentioned phenotypes. Since there are multiple studies in the field of Lowe Syndrome that shed light on the various functions of OCRL, both catalytic and non-catalytic, it is important to address the role of OCRL in resulting in these phenotypes.
(5) There are numerous errors in the qPCR experiments performed with regard to the genes that were assayed. The genes mentioned in the text section do not match those indicated in the graphs or legends. This takes away the confidence of the reader in this data.
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Reviewer #2 (Public review):
Summary:
This manuscript investigates how neural cell development is affected in Lowe syndrome. Using neural cultures differentiated from human iPSCs carrying either an LS mutation or a genetically engineered mutation in OCRL, the authors show a depletion of mitochondrial DNA and a decrease in mitochondrial activities that correlate with an increased formation of astrocytes at the expense of neurons. Similar effects on mitochondria and on astrocyte development were observed in an LS mouse model. Moreover, these mutant brain cells are less likely to be ciliated and show a reduction in Sonic Hedgehog signalling.
Strengths/Weaknesses:
The study derives strength from the analyses of two different models of Lowe syndrome, both reaching similar conclusions. However, the observed changes in mitochondrial defects, …
Reviewer #2 (Public review):
Summary:
This manuscript investigates how neural cell development is affected in Lowe syndrome. Using neural cultures differentiated from human iPSCs carrying either an LS mutation or a genetically engineered mutation in OCRL, the authors show a depletion of mitochondrial DNA and a decrease in mitochondrial activities that correlate with an increased formation of astrocytes at the expense of neurons. Similar effects on mitochondria and on astrocyte development were observed in an LS mouse model. Moreover, these mutant brain cells are less likely to be ciliated and show a reduction in Sonic Hedgehog signalling.
Strengths/Weaknesses:
The study derives strength from the analyses of two different models of Lowe syndrome, both reaching similar conclusions. However, the observed changes in mitochondrial defects, neuronal/astrocytic development, and primary cilia are only correlated, with no attempt to investigate a causal relationship. Moreover, the mouse model is only analysed at the adult stage providing no insights into the development of the defects. Different brain regions are analysed with immunostainings and qRT-PCR making it challenging to draw clear correlations between these findings. The quality of the corresponding figures is often poor and the selection of markers is frequently inappropriate. Taken together, these limitations complicate the interpretations of the data and significantly limit the conclusions that can be drawn from the study.
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